Treatment of stuttering and other communication disorders with norepinephrine reuptake inhibitors

ABSTRACT

Provided are methods and medicaments for treating stuttering or another communication disorder, comprising administering to a patient in need of such treatment an effective amount of a selective norepinephrine reuptake inhibitor.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to the fields of pharmaceutical chemistryand central nervous system medicine. More specifically, the presentinvention relates to methods of treating communication disorders, suchas stuttering, in children, adolescents, and adults by administeringselective norepinephrine reuptake inhibitors to patients in need of suchtreatment.

2. Description of Related Art

The Diagnostic and Statistical Manual ofMental Disorders, Fourth Edition(DSM-IV) (1994), American Psychiatric Association, Washington, D.C., pp.55-65, describes a number of communication disorders usually firstdiagnosed in infancy, childhood, or adolescence. These includestuttering, expressive language disorder, mixed receptive-expressivelanguage disorder, phonological disorder, and communication disorder nototherwise specified. Stuttering is perhaps the most well known of thesedisorders.

Stuttering is a speech disorder in which the normal flow of speech isdisrupted by frequent repetitions or prolongations of speech sounds,syllables, or words, or by an individual's inability to start a word.The speech disruptions may be accompanied by rapid eye blinks, tremorsof the lips and/or jaw, or other struggle behaviors of the face or upperbody that a person who stutters may use in an attempt to speak. Certainsituations, such as speaking before a group of people or talking on thetelephone, tend to make stuttering more severe, whereas othersituations, such as singing or speaking alone, often improve fluency.Stuttering is also referred to as stammering, especially in England, andby a broader term, dysfluent speech.

Characteristics of stuttering are described in Section 307.0 of theDSM-IV at pp. 63-65. While all individuals are dysfluent at times, theperson who stutters is differentiated from someone with normal speechdisfluencies by the kind and amount of dysfluencies.

Characteristics of stuttering include:

-   -   Repetition of sounds, syllables, parts of words, whole words,        and phrases    -   Prolongation, or stretching, of sounds or syllables    -   Tense pauses, hesitations, and/or no sound between words    -   Speech that occurs in spurts, as the client tries to initiate or        maintain voice    -   Related behaviors, for example reactions that accompany        stuttering such as tense muscles in the lips, jaw, and/or neck;        tremor of the lips, jaw, and/or tongue during attempts to speak;        foot tapping, eye blinks, head turns, etc. (to try to escape        from the stuttering); etc. There are many related behaviors that        can occur and vary from person to person.    -   Variability in stuttering behavior, depending on the speaking        situation, the communication partner(s), and the speaking task.        A person who stutters may experience more fluency in the        speech-language pathologist's office than in a classroom or        workplace. There may be no difficulty making a special dinner        request at home, but extreme difficulty ordering a meal in a        restaurant. Conversation with a spouse may be easier, and more        fluent, than that with a boss. A person may be completely fluent        when singing, but experience significant stuttering when talking        on the telephone.    -   A feeling of loss of control. The person who stutters may        experience sound and word fears, situational fears, anticipation        of stuttering, embarrassment, and a sense of shame. Certain        sounds or words may be avoided. One word may be substituted for        another that is thought to be harder to say. Or, certain        speaking situations may be avoided altogether. For example, a        person who stutters may always wait for someone else to answer        the phone. Or, he or she may walk around a store for an hour        rather than ask sales staff where an item can be found. These        reactions to stuttering occur in more advanced stages.

Repetitions and prolongations are essential features of stuttering. Thepresence of the other listed behaviors varies from person to person.

Developmental stuttering (DS), with or without associated psychiatricillness, is the most common form, and includes all cases with gradualonset in childhood that are not the result of acquired brain damage.Persistent developmental stuttering (PDS) is DS that has not undergonespontaneous or speech therapy-induced remission. Acquired stuttering,which is much rarer than DS, may occur in previously fluent individuals.This form may be neurogenic, resulting from brain damage associatedwith, for example, stroke, traumatic brain injury, Alzheimer's disease,renal dialysis, Parkinson's disease, and progressive supranuclear palsy(Heuer et al. (1996) Ear Nose Throat J. 75:161-168; Brazis et al. (1996)Localization in Clinical Neurology, Third Ed., Little, Brown andCompany, Boston, Mass., p.515).

Based on neuroimaging research data and the effectiveness of dopaminereceptor antagonists in DS, this form of stuttering appears to have ahyperdopaminergic origin.

It is estimated that over three million Americans stutter. Stutteringaffects individuals of all ages, but occurs most frequently in youngchildren between the ages of 2 and 6 who are developing language. Theprevalence of stuttering in prepubertal children is 1%, and drops to0.8% in adolescence. The male-to-female ratio is approximately 3: 1.Most children outgrow their stuttering, and it is estimated that lessthan 1 percent of adults stutter.

Family and twin studies strongly suggest a genetic factor in theetiology of stuttering. The risk of stuttering among first-degreebiological relatives is more than three times that in the generalpopulation. About 10% of daughters, and 20% of sons, of men who stutterwill also stutter.

There is at present no cure for stuttering. However, a variety oftreatments are available that may improve stuttering to some degree.These include speech therapy to improve fluency and success incommunication; parent education to restructure the child's speakingenvironment to reduce episodes of stuttering; and the use ofinterventions such as electronic devices or medications. Electronicdevices which help an individual control fluency may be more of a botherthan a help in most speaking situations, and are often abandoned byindividuals who stutter. Medications that affect brain function oftenhave side effects that make them difficult to use for long-termtreatment.

Many medications have been studied for use in treating stuttering.Evidence suggests that persons who stutter exhibit hypometabolism of thestriatum and increased dopamine activity (Wu et al. (1995) Neuroreport6:501-5; Wu et al. (1997) Neuroreport 8:767-70; Wu et al. (1997) In:Hulstijn W, Peters HRM, van Lieshout PHHM, eds. Speech production: motorcontrol, brain research and fluency disorders. International CongressSeries 1146. Amsterdam: Excerpta Medica 339-41). Drugs that boostdopamine levels exacerbate stuttering. Ritalin has a similar effect.Tricyclic antidepressants have proved ineffective, and in factstuttering has been reported as an adverse event with the use of thesecompounds.

In contrast, the dopamine antagonist haloperidol has been shown inreplicated, double-blind trials to reduce the symptoms of stuttering,leading to the hypothesis that D₂ receptor antagonists may be importantin the treatment of developmental stuttering (J. P. Brady (1991) Am. J.Psychiatry 148:1309-16). Unfortunately, as this drug is not welltolerated by this patient population and carries substantial risk ofextrapyramidal symptoms and tardive dyskinesia, it is not recommendedfor the treatment of stuttering.

In a recent small study, Maguire et al. ((2000) J. Clin.Psychopharmacology 20:479-482) demonstrated that the serotonin-dopamineantagonist risperidone may be effective in the treatment ofdevelopmental stuttering, and recommended further investigations ofrisperidone for this purpose. While extrapyramidal symptoms andakathisia were not found with the use of risperidone, sedation wascommon, and some participants developed transient sexual and menstrualcycle side effects that resolved with discontinuance of the medication,or with a reduction in dose. These side effects are thought to be due tothe elevation of the hormone prolactin by risperidone (haloperidol alsoraises prolactin levels in some patients).

Paroxetine and Sertraline, selective serotonin reuptake inhibitors, arealso used for the treatment of stuttering, but cause a number ofundesirable side effects.

Newer medications more narrowly target dopamine receptors. Olanzapine(Zyprexa), has been used successfully to treat developmental andacquired stuttering in children, adolescents, and adults (Lavid et al.(1999) Annals of Clinical Psychiatry 11(4): 233-236; Lavid et al. (2000)Presented at the annual meeting of the American Psychiatric Association,Chicago III., 2000). Side effects were mostly limited to slight weightgain and drowsiness.

The present invention addresses the need in the art for improvedtreatments for stuttering that are both safe and effective.

SUMMARY OF THE INVENTION

Accordingly, in a first aspect, the present invention provides a methodof treating stuttering or another communication disorder, comprisingadministering to a patient in need of such treatment an effective amountof a selective norepinephrine reuptake inhibitor. The selectivenorepinephrine reuptake inhibitor can be, but is not limited to, any ofthe compounds disclosed herein.

In another aspect, the present invention provides the use of a selectivenorepinephrine reuptake inhibitor, such as any of the compoundsdisclosed herein, or other selective norepinephrine reuptake inhibitors,for the manufacture of a medicament for the treatment of stuttering oranother communication disorder.

Further scope of the applicability of the present invention will becomeapparent from the detailed description provided below. However, itshould be understood that the detailed description and specificexamples, while indicating preferred embodiments of the presentinvention, are given by way of illustration only since various changesand modifications within the spirit and scope of the invention willbecome apparent to those skilled in the art from this detaileddescription.

DETAILED DESCRIPTION OF THE INVENTION

The following detailed description of the invention is provided to aidthose skilled in the in practicing the present invention. Even so, thefollowing detailed description should not be construed to unduly limitthe present invention as modifications and variations in the embodimentsdiscussed herein can be made by those of ordinary skill in the artwithout departing from the spirit or scope of the present inventivediscovery.

The contents of each of the references cited herein are hereinincorporated by reference in their entirety.

Costa and Kroll ((2000) Canadian Medical Association Journal162(13):1849-1855) disclose definitions and features of the varioustypes of stuttering:

Developmental Stuttering—Stuttering with gradual onset in childhood as adisturbance in the normal fluency and time patterning of speech.

Persistent Developmental Stuttering—Developmental stuttering that hasnot undergone spontaneous or speech therapy-induced remission.

Acquired Stuttering—Stuttering that occurs more or less abruptly inpreviously fluent individuals. Neurogenic acquired stuttering resultsfrom brain damage, involves repetitions, prolongations, and blocks, andis not associated with grimaces, eye-blinking, or social anxiety.Psychogenic acquired stuttering begins suddenly after emotional trauma,and involves repetition of initial or stressed syllables, indifferencetoward dysfluency, dysfluency that never fluctuates, and persistence ofnormal eye contact.

Diagnostic criteria for stuttering set forth in the DSM-IV (p. 65) are:

Diagnostic Criteria for 307.0 Stuttering

A. Disturbance in the normal fluency and time patterning of speech(inappropriate for the individual's age), characterized by frequentoccurrences of one or more of the following:

(1) sound and syllable repetitions

(2) sound prolongations

(3) interjections

(4) broken words (e.g., pauses within a word)

(5) audible or silent blocking (filled or unfilled pauses in speech)

(6) circumlocutions (word substitutions to avoid problematic words)

(7) words produced with an excess of physical tension

(8) monosyllabic whole-word repetitions (e.g., “I-I-I-1 see him”)

B. The disturbance in fluency interferes with academic or occupationalachievement or with social communication.

C. If a speech-motor or sensory deficit is present, the speechdifficulties are in excess of those usually associated with theseproblems.

Any of the types of stuttering described above, whether presentingalone, or comorbidly with cluttering, phonological disorder, expressiveor mixed receptive-expressive language disorder, attention-deficithyperactivity disorder (ADHD), or mental retardation, can be treated orprevented by the methods of the present invention. Patients will receivebenefit from the use of norepinephrine reuptake inhibitors in theamelioration of the symptoms of stuttering regardless of whether acomorbid condition is present. Patients suffering from both stutteringand a comorbid condition, for example attention-deficit hyperactivitydisorder, will receive benefit in the amelioration of symptoms of bothconditions via the methods of the present invention. Therefore, inaddition to methods for treating stuttering presenting alone, thepresent invention encompasses methods of treating stuttering comorbidwith any of the conditions listed immediately above, comprisingadministering to a patient in need of treatment of both stuttering andsuch comorbid condition an effective amount of a selectivenorepinephrine reuptake inhibitor.

For clarification, cluttering is characterized by unpredictable, fast,and jerky outpourings of words and phrases, including slurred or omittedsyllables and improper phrasing and pauses (Kaplan and Sadock (1998)Synopsis of Psychiatry, Eighth Ed., Williams and Wilkins, Baltimore,Md., pp. 1175-7). Phonological disorder (DSM-IV section 315.39)involves, in part, failure to produce developmentally expected speechsounds appropriate for the individual's age and dialect, and can involveerrors in sound production, use, representation, or organization.Expressive language disorder (DSM-IV section 315.31) involves, in part,an impairment in expressive language development as demonstrated byscores on standardized individually administered measures of expressivelanguage development substantially below those obtained fromstandardized measures of both nonverbal intellectual capacity andreceptive language development. Mixed receptive-expressive languagedisorder (DSM-IV section 315.32) involves, in part, an impairment inboth receptive and expressive language development as demonstrated byscores on standardized individually administered measures of bothreceptive and expressive language development that are substantiallybelow those obtained from standardized measures of nonverbalintellectual capacity. Attention-deficit hyperactivity disorder (DSM-IVsections 314.00 and 314.01) involves, in part, a persistent pattern ofinattention and/or hyperactivity-impulsivity that is more frequent andsevere than is typically observed in individuals at a comparable levelof development.

Specific diagnostic criteria in the DSM-IV for expressive languagedisorder, mixed receptive-expressive language disorder, phonologicaldisorder, communication disorder not otherwise specified, as well as forattention-deficit hyperactivity disorder, each of which can existcomorbidly with developmental stuttering, are as follows:

Diagnostic Criteria for 315.31 Expressive Language Disorder

A. The scores obtained from standardized individually administeredmeasures of expressive language development are substantially belowthose obtained from standardized measures of both nonverbal intellectualcapacity and receptive language development. The disturbance may bemanifest clinically by symptoms that include having a markedly limitedvocabulary, making errors in tense, or having difficulty recalling wordsor producing sentences with developmentally appropriate length orcomplexity.

B. The difficulties with expressive language interfere with academic oroccupational achievement or with social communication.

C. Criteria are not met for Mixed Receptive-Expressive Language Disorderor a Pervasive Developmental Disorder.

D. If Mental Retardation, a speech-motor or sensory deficit, orenvironmental deprivation is present, the language difficulties are inexcess of those usually associated with these problems.

Diagnostic Criteria for 315.32 Mixed Receptive-Expressive LanguageDisorder

A. The scores obtained from a battery of standardized individuallyadministered measures of both receptive and expressive languagedevelopment are substantially below those obtained from standardizedmeasures of nonverbal intellectual capacity. Symptoms include those forExpressive Language Disorder as well as difficulty understanding words,sentences, or specific types of words, such as spatial terms.

B. The difficulties with receptive and expressive language significantlyinterfere with academic or occupational achievement or with socialcommunication.

C. Criteria are not met for a Pervasive Developmental Disorder.

D. If Mental Retardation, a speech-motor or sensory deficit, orenvironmental deprivation is present, the language difficulties are inexcess of those usually associated with these problems.

Diagnostic Criteria for 315.39 Phonological Disorder

A. Failure to use developmentally expected speech sounds that areappropriate for age and dialect (e.g., errors in sound production, use,representation, or organization such as, but not limited to,substitutions of one sound for another [use of /t/ for target /k/ sound]or omissions of sounds such as final consonants).

B. The difficulties in speech sound production interfere with academicor occupational achievement or with social communication.

C. If Mental Retardation, a speech-motor or sensory deficit, orenvironmental deprivation is present, the speech difficulties are inexcess of those usually associated with these problems.

307.9 Communication Disorder Not Otherwise Specified

This category is for disorders in communication that do not meetcriteria for any specific Communication Disorder; for example, a voicedisorder (i.e., an abnormality of vocal pitch, loudness, quality, tone,or resonance).

Diagnostic Criteria for Attention-Deficit/Hyperactivity Disorder

A. Either (1) or (2):

(1) six (or more) of the following symptoms of inattention havepersisted for at least 6 months to a degree that is maladaptive andinconsistent with developmental level:

Inattention

(a) often fails to give close attention to details or makes carelessmistakes in schoolwork, work, or other activities

(b) often has difficulty sustaining attention in tasks or playactivities

(c) often does not seem to listen when spoken to directly

(d) often does not follow through on instructions and fails to finishschoolwork, chores, or duties in the workplace (not due to oppositionalbehavior or failure to understand instructions)

(e) often has difficulty organizing tasks and activities

(f) often avoids, dislikes, or is reluctant to engage in tasks thatrequire sustained mental effort (such as schoolwork or homework)

(g) often loses things necessary for tasks or activities (e.g., toys,school assignments, pencils, books, or tools)

(h) is often easily distracted by extraneous stimuli

(i) is often forgetful in daily activities

(2) six (or more) of the following symptoms of hyperactivity-impulsivityhave persisted for at least 6 months to a degree that is maladaptive andinconsistent with developmental level:

Hyperactivity

(a) often fidgets with hands or feet or squirms in seat

(b) often leaves seat in classroom or in other situations in whichremaining seated is expected

(c) often runs about or climbs excessively in situations in which it isinappropriate (in adolescents or adults, may be limited to subjectivefeelings of restlessness)

(d) often has difficulty playing or engaging in leisure activitiesquietly

(e) is often “on the go” or often acts as if “driven by a motor”

(f) often talks excessively

Impulsivity

(g) often blurts out answers before questions have been completed

(h) often has difficulty awaiting turn

(i) often interrupts or intrudes on others (e.g., butts intoconversations or games)

B. Some hyperactive-impulsive or inattentive symptoms that causedimpairment were present before age 7 years.

C. Some impairment from the symptoms is present in two or more settings(e.g., at school [or work] and at home).

D. There must be clear evidence of clinically significant impairment insocial, academic, or occupational functioning.

E. The symptoms do not occur exclusively during the course of aPervasive Developmental Disorder, Schizophrenia, or other PsychoticDisorder and are not better accounted for by another mental disorder(e.g., Mood Disorder, Anxiety Disorder, Dissociative Disorder, or aPersonality Disorder).

Code based on type:

314.01 Attention-Deficit/Hyperactivity Disorder, Combined Type: if bothCriteria A1 and A2 are met for the past 6 months

314.00 Attention-Deficit/Hyperactivity Disorder, PredominantlyInattentive Type: if Criterion A1 is met but Criterion A2 is not met forthe past 6 months

314.01 Attention-Deficit/Hyperactivity Disorder, PredominantlyHyperactive-Impulsive Type: if Criterion A2 is met but Criterion A1 isnot met for the past 6 months

The methods of the present invention are effective in the treatment ofpatients who are children, adolescents, or adults, and there is nosignificant difference in the symptoms or the details of the manner oftreatment among patients of different ages. In general terms, forpurposes of the present invention, a child is considered to be a patientbelow the age of puberty, an adolescent is considered to be a patientfrom the age of puberty up to about 18 years of age, and an adult isconsidered to be a patient of 18 years or older.

Norepinephrine Reuptake Inhibitors Useful in the Present Invention

To the best of the inventor's knowledge, norepinephrine reuptakeinhibitors have not been employed to treat stuttering.

Many compounds, including those discussed at length below, are selectivenorepinephrine reuptake inhibitors, and no doubt many more will beidentified in the future. Practice of the present invention encompassesthe use of norepinephrine reuptake inhibitors that exhibit 50% effectiveconcentrations of about 1000 nM or less in the protocol described byWong et al. (1985) Drug Development Research, 6:397. Preferrednorepinephrine reuptake inhibitors useful in the methods of the presentinvention are those that are selective for the inhibition ofnorepinephrine reuptake relative to their ability to act as directagonists or antagonists at other receptors. Preferably, the compoundsuseful in the methods of the present invention are selective for theinhibition of norepinephrine reuptake relative to direct agonist orantagonist activity at other receptors by a factor of at least ten, andeven more preferably by a factor of at least one hundred.

Norepinephrine reuptake inhibitors useful in the methods of the presentinvention include, but are not limited to:

1. Atomoxetine (formerly known as tomoxetine),(R)-(−)-N-methyl-3-(2-methyl-phenoxy)-3-phenylpropylamine, is usuallyadministered as the hydrochloride salt. Atomoxetine was first disclosedin U.S. Pat. No. 4,314,081. The term “atomoxetine” will be used here torefer to any acid addition salt or the free base of the molecule. See,for example, Gehiert et al. (1993) Neuroscience Letters 157:203-206, fora discussion of atomoxetine's activity as a norepinephrine reuptakeinhibitor;

2. Reboxetine (Edronax™; Prolift™; Vestra™; Norebox™),2-[α-(2-ethoxy)phenoxy-benzyl]morpholine, first disclosed in U.S. Pat.No. 4,229,449 for the treatment of depression, is usually administeredas the racemate. Reboxetine is a selective norepinephrine reuptakeinhibitor. The term “reboxetine” as used herein refers to any acidaddition salt or the free base of the molecule existing as the racemateor either enantiomer, i.e., (S,S)-reboxetine or (R,R)-reboxetine. Theuse of (S,S)-reboxetine as a preferred selective norepinephrine reuptakeinhibitor is disclosed in PCT International Publication No. WO 01/01973.

3. Compounds of formula I:

wherein X is C₁-C₄ alkylthio, and Y is C₁-C₂ alkyl or a pharmaceuticallyacceptable salt thereof. The compounds of formula 1 have been describedin U.S. Pat. No. 5,281,624, and in Gehlert et al. (1 995) Life Sciences,55(22):1915-1920. These compounds are disclosed as being inhibitors ofnorepinephrine reuptake in the brain. It should be noted that thesecompounds exist as stereoisomers, and accordingly include not only theracemates, but also the isolated individual isomers as well as mixturesof the individual isomers. For example, the compounds of formula 1include the following exemplary species:

N-ethyl-3-phenyl-3-(2-methylthiophenoxy)propyl-amine benzoate;

(R)-N-methyl-3-phenyl-3-(2-propylthiophenoxy)-propylamine hydrochloride;

(S)-N-ethyl-3-phenyl-3-(2-butylthiophenoxy)propyl-amine;

N-methyl-3-phenyl-3-(2-ethylthiophenoxy)propyl-amine malonate;

(S)-N-methyl-3-phenyl-3-(2-tert-butylthiophenoxy)-propylaminenaphthalene-2-sulfonate; and

(R)-N-methyl-3-(2-methylthiophenoxy)-3-phenyl-propylamine.

4. A compound of formula (IA)

wherein n is 1, 2 or 3; R¹ is C₂-C₁₀alkyl, C2-C₁₀alkenyl,C₃-C₈cycloalkyl or C₄-C₁₀cycloalkylalkyl, wherein one C—C bond withinany cycloalkyl moiety is optionally substituted by an O—C or C═C bondand wherein each group is optionally substituted with from 1 to 7halogen substituents and/or with from 1 to 3 substituents eachindependently selected from hydroxy, cyano, C₁-C₄alkyl and C₁-C₄alkoxy;R2 is H, C₁-C₄alkyl (optionally substituted with from 1 to 7 halogenatoms), C₁-C₄alkyl-S(O)_(x)— wherein x is 0, 1 or 2 (optionallysubstituted with from 1 to 7 halogen atoms), C₁-C₄alkoxy (optionallysubstituted with from 1 to 7 halogen atoms), cyano, halogen, phenyl(optionally substituted with from 1 to 3 substituents each independentlyselected from halogen, C₁-C₄alkyl and C₁-C₄alkoxy), phenoxy (optionallysubstituted with from 1 to 3 substituents each independently selectedfrom halogen, C₁-C₄alkyl and C₁-C₄alkoxy) or —CO₂(C₁-C₄alkyl), ortogether with R3 forms a further benzene ring (optionally substitutedwith from 1 to 3 substituents each independently selected from halogen,C₁-C₄alkyl and C₁-C₄alkoxy); R3 is H, C₁-C₄alkyl (optionally substitutedwith from 1 to 7 halogen atoms), C₁-C₄alkyl-S(O)_(x)— wherein x is 0, 1or 2 (optionally substituted with from 1 to 7 halogen atoms),C₁-C₄alkoxy (optionally substituted with from 1 to 7 halogen atoms),cyano, halogen, phenyl (optionally substituted with from 1 to 3substituents each independently selected from halogen, C₁-C₄alkyl andC₁-C₄alkoxy), phenoxy (optionally substituted with from 1 to 3substituents each independently selected from halogen, C₁-C₄alkyl andC₁-C₄alkoxy) or —CO₂(C₁-C₄alkyl), or together with R2 or R4 forms afurther benzene ring (optionally substituted with from 1 to 3substituents each independently selected from halogen, C₁-C₄alkyl andC₁-C₄alkoxy); R4 is H, C₁-C₄alkyl (optionally substituted with from 1 to7 halogen atoms), C₁-C₄alkyl-S(O)_(x)— wherein x is 0, 1 or 2(optionally substituted with from 1 to 7 halogen atoms), C₁-C₄alkoxy(optionally substituted with from 1 to 7 halogen atoms), cyano, halogen,phenyl (optionally substituted with from 1 to 3 substituents eachindependently selected from halogen, C₁-C₄alkyl and C₁-C₄alkoxy),phenoxy (optionally substituted with from 1 to 3 substituents eachindependently selected from halogen, C₁-C₄alkyl and C₁-C₄alkoxy) or—CO₂(C₁-C₄alkyl), or together with R3 forms a further benzene ring(optionally substituted with from 1 to 3 substituents each independentlyselected from halogen, C₁-C₄alkyl and C₁-C₄alkoxy); R5 is H, C₁-C₄alkyl(optionally substituted with from 1 to 7 halogen atoms), C₁-C₄alkoxy(optionally substituted with from 1 to 7 halogen atoms) or halogen; R6is H, C₁-C₄alkyl (optionally substituted with from 1 to 7 halogenatoms), C₁-C₄alkoxy (optionally substituted with from 1 to 7 halogenatoms) or halogen; R7 is H or C₁-C₄alkyl; R8 is H or C₁-C₄alkyl; R9 isH, halogen, hydroxy, cyano, C₁-C₄alkyl or C₁-C₄alkoxy; and R10 is H,halogen, hydroxy, cyano, C₁-C₄alkyl or C₁-C₄alkoxy; or apharmaceutically acceptable salt thereof, with the proviso that thecompound N-ethyl-N-benzyl-4-piperidinamine is excluded.

With respect to compounds of formula (IA), the term “C₂-C₁₀alkyl” meansa monovalent unsubstituted saturated straight-chain or branched-chainhydrocarbon radical having from 2 to 10 carbon atoms.

With respect to compounds of formula (IA), the term “C₂-C₁₀alkenyl”means a monovalent unsubstituted unsaturated straight-chain orbranched-chain hydrocarbon radical having from 2 to 10 carbon atoms andcontaining at least one carbon-carbon double bond.

With respect to compounds of formula (IA), the term “C₃-C₈cycloalkyl”means a monovalent unsubstituted saturated cyclic hydrocarbon radicalhaving from 3 to 8 carbon atoms.

With respect to compounds of formula (IA), the term“C₄-C₁₀cycloalkylalkyl” means a monovalent unsubstituted saturatedcyclic hydrocarbon radical having from 3 to 9 carbon atoms linked to thepoint of substitution by a divalent unsubstituted saturatedstraight-chain or branched-chain hydrocarbon radical having at least 1carbon atom.

With respect to compounds of formula (IA), the phrase “wherein one C—Cbond within any cycloalkyl moiety is optionally substituted by an O—C orC═C bond” means that either (i) any two adjacent carbon atoms within acycloalkyl ring may be linked by a double bond rather than a single bond(with the number of substituents on each carbon atom being reducedaccordingly), or that (ii) one of any two adjacent C atoms within acycloalkyl ring (and any substituents thereon) may be replaced by anoxygen atom. Examples of R¹ groups encompassed by this phrase includebut are not limited to:

With respect to compounds of formula (IA), the term “halo” or “halogen”means F, Cl, Br or I.

With respect to compounds of formula (IA), the term “C₁-C₄alkoxy” meansa monovalent unsubstituted saturated straight-chain or branched-chainhydrocarbon radical having from 1 to 4 carbon atoms linked to the pointof substitution by an O atom.

With respect to compounds of formula (IA), the term “phenoxy” means amonovalent unsubstituted phenyl radical linked to the point ofsubstitution by an O atom.

With respect to compounds of formula (IA), in the above definitions,similar terms specifying different numbers of C atoms take an analogousmeaning.

Preferred compounds of formula (IA) are those wherein n is 1 or 2. Morepreferably, n is 1.

Preferred compounds of formula (IA) are those wherein R7 is H or methyl.More preferably R7 is H.

Preferred compounds of formula (IA) are those wherein R8 is H.

Preferred compounds of formula (IA) are those wherein R9 is H or fluoro.More preferably, R9 is H.

Preferred compounds of formula (IA) are those wherein R10 is H orfluoro. More preferably, R10 is H.

Preferred compounds of formula (IA) are those wherein R¹ is C₂-C₆alkyl,C₂-C₆alkenyl, C₃-C₆cycloalkyl or C₄-C₇cycloalkylalkyl, each of which isoptionally substituted with from 1 to 3 halogen atoms or a methoxyradical. More preferably, R¹ is C₂-C₆alkyl (optionally substituted withfrom 1 to 3 halogen atoms or a methoxy radical), C₂-C₆alkenyl,C₃-C₆cycloalkyl or C₄-C₇cycloalkylalkyl. Suitable C₂-C6alkyl groups(optionally substituted with from 1 to 3 halogen atoms or a methoxyradical) include, for example, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, n-pentyl, 3-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl,3,3-dimethylbutyl, 2-ethylbutyl, 3,3,3-trifluoropropyl,4,4,4-trifluorobutyl and 2-methoxyethyl. Suitable C₂-C₆alkenyl groupsinclude, for example, 2-metbyl-2-propenyl. Suitable C₃-C₆cycloalkylgroups include, for example, cyclopentyl. Suitable C₄-C₇cycloalkylalkylgroups include, for example, cyclohexylmethyl or cyclopropylmethyl.

Preferred compounds of formula (IA) are those wherein R¹ is aC₂-C₁₀alkyl group optionally substituted with from 1 to 7 halogensubstituents and/or with from 1 to 3 substituents each independentlyselected from hydroxy, cyano and C₁-C₄alkoxy. More preferably, R¹ is aC₂-CIoalkyl group optionally substituted with from 1 to 3 substituentseach independently selected from halogen, hydroxy and C₁-C₄alkoxy. Morepreferably R¹ is C₂-C₆alkyl optionally substituted with from 1 to 3halogen atoms or a methoxy radical. Still more preferably R¹ isC₂-C₆alkyl. Still more preferably, Rl is selected from ethyl, n-propyl,isopropyl, n-butyl, isobutyl, n-pentyl, 3-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, 3,3-dimethylbutyl and 2-ethylbutyl.Most preferably R¹ is selected from n-propyl, n-butyl and isobutyl.

Preferred compounds of formula (IA) are those wherein R2 is H,C₁-C₄alkyl (optionally substituted with from 1 to 7 halogen atoms),C₁-C₄alkyl-S(O)_(x)— wherein x is 0 or 2 (optionally substituted withfrom 1 to 7 halogen atoms), C₁-C₄alkoxy (optionally substituted withfrom 1 to 7 halogen atoms), cyano, halogen, phenyl (optionallysubstituted with from 1 to 3 substituents each independently selectedfrom halogen, C₁-C₄alkyl and C₁-C₄alkoxy) or phenoxy (optionallysubstituted with from 1 to 3 substituents each independently selectedfrom halogen, C₁-C₄alkyl and C₁-C₄alkoxy), or together with R3 forms afurther benzene ring (optionally substituted with from 1 to 3substituents each independently selected from halogen, C₁-C₄alkyl andC₁-C₄alkoxy). More preferably, R2 is H, C₁-C₂alkyl (optionallysubstituted with from 1 to 5 halogen atoms), C₁-C₄alkyl-S(O)_(x)—wherein x is 0 or 2 (optionally substituted with from 1 to 5 halogenatoms), C₁-C₂alkoxy (optionally substituted with from 1 to 5 halogenatoms), cyano, halogen, phenyl (optionally substituted with from 1 to 3substituents each independently selected from halogen, C₁-C₂alkyl andC₁-C₂alkoxy) or phenoxy (optionally substituted with from 1 to 3substituents each independently selected from halogen, C₁-C₂alkyl andC₁-C₂alkoxy), or together with R3 forms a further benzene ring(optionally substituted with from 1 to 3 substituents each independentlyselected from halogen, C₁-C₂alkyl and C₁-C₂alkoxy). Still morepreferably, R2 is H, methyl, trifluoromethyl, methylthio,tert-butylthio, trifluoromethylthio, methylsulfonyl, methoxy, ethoxy,difluoromethoxy, trifluoromethoxy, cyano, fluoro, chloro, bromo, phenylor phenoxy, or together with R3 forms a further benzene ring.

Preferred compounds of formula (IA) are those wherein R2 is not H. Morepreferably, R2 is C₁-C₄alkyl (optionally substituted with from 1 to 7halogen atoms), C₁-C₄alkyl-S(O)_(x)— wherein x is 0 or 2 (optionallysubstituted with from 1 to 7 halogen atoms), C₁-C₄alkoxy (optionallysubstituted with from 1 to 7 halogen atoms), cyano, halogen, phenyl(optionally substituted with from 1 to 3 substituents each independentlyselected from halogen, C₁-C₄alkyl and C₁-C₄alkoxy) or phenoxy(optionally substituted with from 1 to 3 substituents each independentlyselected from halogen, C₁-C₄alkyl and C₁-C₄alkoxy), or together with R3forms a further benzene ring (optionally substituted with from 1 to 3substituents each independently selected from halogen, C₁-C₄alkyl andC₁-C₄alkoxy). More preferably, R2 is C₁-C₂alkyl (optionally substitutedwith from 1 to 5 halogen atoms), C₁-C₂alkyl-S(O)_(x)— wherein x is 0 or2 (optionally substituted with from 1 to 5 halogen atoms), C₁-C₂alkoxy(optionally substituted with from 1 to 5 halogen atoms), cyano, halogen,phenyl (optionally substituted with from 1 to 3 substituents eachindependently selected from halogen, C₁-C₂alkyl and C₁-C₂alkoxy) orphenoxy (optionally substituted with from 1 to 3 substituents eachindependently selected from halogen, C₁-C₂alkyl and C₁-C₂alkoxy), ortogether with R3 forms a further benzene ring (optionally substitutedwith from 1 to 3 substituents each independently selected from halogen,C₁-C₂alkyl and C₁-C₂alkoxy). Still more preferably, R2 is methyl,trifluoromethyl, methylthio, tert-butylthio, trifluoromethylthio,methylsulfonyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy,cyano, fluoro, chloro, bromo, phenyl or phenoxy, or together with R3forms a further benzene ring.

Preferred compounds of formula (IA) are those wherein R3 is H,C₁-C₄alkyl (optionally substituted with from 1 to 7 halogen atoms),C₁-C₄alkyl-S— (optionally substituted with from 1 to 7 halogen atoms),C₁-C₄alkoxy (optionally substituted with from 1 to 7 halogen atoms),cyano, halogen, phenyl (optionally substituted with from 1 to 3substituents each independently selected from halogen, C₁-C₄alkyl andC₁-C₄alkoxy), phenoxy (optionally substituted with from 1 to 3substituents each independently selected from halogen, C₁-C₄alkyl andC₁-C₄alkoxy) or —CO₂(C₁-C₄alkyl), or together with R2 or R4 forms afurther benzene ring (optionally substituted with from 1 to 3substituents each independently selected from halogen, C₁-C₄alkyl andC₁-C₄alkoxy). More preferably, R3 is H, C₁-C₂alkyl (optionallysubstituted with from 1 to 5 halogen atoms), C₁-C₂alkyl-S— (optionallysubstituted with from 1 to 5 halogen atoms), C₁-C₂alkoxy (optionallysubstituted with from 1 to 5 halogen atoms), cyano, halogen, phenyl(optionally substituted with from 1 to 3 substituents each independentlyselected from halogen, C₁-C₂alkyl and C₁-C₂alkoxy), phenoxy (optionallysubstituted with from 1 to 3 substituents each independently selectedfrom halogen, C₁-C₂alkyl and C₁-C₂alkoxy) or —CO₂(C₁-C₂alkyl), ortogether with R2 or R4 forms a further benzene ring (optionallysubstituted with from 1 to 3 substituents each independently selectedfrom halogen, C₁-C₂alkyl and C₁-C₂alkoxy). Still more preferably, R3 isH, methyl, trifluoromethyl, trifluoromethylthio, methoxy, ethoxy,difluoromethoxy, trifluoromethoxy, cyano, fluoro, chloro, bromo, phenyl,phenoxy or CO₂CH₃, or together with R2 or R4 forms a further benzenering.

Preferred compounds of formula (IA) are those wherein R4 is H,C₁-C₄alkyl (optionally substituted with from 1 to 7 halogen atoms),C₁-C₄alkyl-S— (optionally substituted with from 1 to 7 halogen atoms),C₁-C₄alkoxy (optionally substituted with from 1 to 7 halogen atoms),cyano, halogen, phenyl (optionally substituted with from 1 to 3substituents each independently selected from halogen, C₁-C₄alkyl andC₁-C₄alkoxy), or —CO₂(C₁-C₄alkyl), or together with R3 forms a furtherbenzene ring (optionally substituted with from 1 to 3 substituents eachindependently selected from halogen, C₁-C₄alkyl and C₁-C₄alkoxy). Morepreferably, R4 is H, C₁-C₂alkyl (optionally substituted with from 1 to 5halogen atoms), C₁-C₂alkyl-S— (optionally substituted with from 1 to 5halogen atoms), C₁-C₂alkoxy (optionally substituted with from 1 to 5halogen atoms), cyano, halogen, phenyl (optionally substituted with from1 to 3 substituents each independently selected from halogen, C₁-C₂alkyland C₁-C₂alkoxy), or —CO₂(C₁-C₂alkyl), or together with R3 forms afurther benzene ring (optionally substituted with from 1 to 3substituents each independently selected from halogen, C₁-C₂alkyl andC₁-C₂alkoxy). Still more preferably, R4 is H, methyl, trifluoromethyl,methylthio, methoxy, trifluoromethoxy, cyano, fluoro, chloro, phenyl orCO₂CH₃, or together with R3 forms a further benzene ring.

Preferred compounds of formula (lA) are those wherein R5 is H,C₁-C₄alkyl (optionally substituted with from 1 to 5 halogen atoms),C₁-C4alkoxy (optionally substituted with from 1 to 5 halogen atoms) orhalogen. More preferably, R5 is H, C₁-C₄alkyl, C₁-C₄alkoxy or halogen.Still more preferably, R5 is H, methyl, methoxy, fluoro or chloro.

Preferred compounds of formula (IA) are those wherein R6 is H,C₁-C₄alkyl (optionally substituted with from 1 to 5 halogen atoms) orhalogen. More preferably, R6 is H, C₁-C₄alkyl or halogen. Still morepreferably, R6 is H, methyl, fluoro or chloro.

Preferred compounds of formula (IA) are those wherein the group

is phenyl, 2-methylphenyl, 2-(trifluoromethyl)phenyl,2-(methylthio)phenyl, 2-(tertbutylthio)phenyl,2-(trifluoromethylthio)phenyl, 2-(methylsulfonyl)phenyl,2-methoxyphenyl, 2-ethoxyphenyl, 2-(difluoromethoxy)phenyl,2-(trifluoromethoxy)phenyl, 2-cyanophenyl, 2-fluorophenyl,2-chlorophenyl, 2-bromophenyl, 2-biphenyl, 2-phenoxyphenyl,3-methylphenyl, 3-(trifluoromethyl)phenyl,3-(trifluoromethylthio)phenyl, 3-methoxyphenyl, 3-ethoxyphenyl,3-(difluoromethoxy)phenyl, 3-(trifluoromethoxy)phenyl, 3-cyanophenyl,3-fluorophenyl, 3-chlorophenyl, 3-bromophenyl, 3-biphenyl,3-phenoxyphenyl, 3-(methoxycarbonyl)phenyl, 4-methylphenyl,4-(trifluoromethyl)phenyl, 4-(methylthio)phenyl, 4-methoxyphenyl,4-(trifluoromethoxy)phenyl, 4-cyanophenyl, 4-fluorophenyl,4-chlorophenyl, 4-biphenyl, 4-(methoxycarbonyl)phenyl,2,3-dichlorophenyl, 2,4-dimethylphenyl, 2,4-bis(trifluoromethyl)phenyl,2,4-dimethoxyphenyl, 2,4-difluorophenyl, 2,4-dichlorophenyl,2,5-dimethylphenyl, 2,6-dimethylphenyl, 2,6-dichlorophenyl,2-chloro-6-fluorophenyl, 2-fluoro-6-(trifluoromethyl)phenyl,3,4-dichlorophenyl, 3,5-dimethylphenyl, 3,5-dimethoxyphenyl,3,5-difluorophenyl, 3,5-dichlorophenyl,3-fluoro-5-(trifluoromethyl)phenyl, 5-fluoro-2-(trifluoromethylphenyl),5-fluoro-2-methoxyphenyl, 4-fluoro-2-(trifluoromethyl)phenyl, 1-naphthylor 2-naphthyl.

A further embodiment provides a group (Group A) of compounds of formula(IA) above, wherein R2, R3, R4, R5 and R6 are all H.

urther embodiment provides a group (Group B) of compounds of formula(IA) above, wherein one of R2, R3, R4, R5 and R6 is not H and the othersare H.

Compounds of Group B include those (Group B2) wherein R3, R4, R5 and R6are all H and R2 is C₁-C₄alkyl (optionally substituted with from 1 to 7halogen atoms), C₁-C₄alkyl-S(O)_(x)— wherein x is 0,1 or 2 (optionallysubstituted with from 1 to 7 halogen atoms), C₁-C₄alkoxy (optionallysubstituted with from 1 to 7 halogen atoms), cyano, halogen, phenyl(optionally substituted with from 1 to 3 substituents each independentlyselected from halogen, C₁-C₄alkyl and C₁-C₄alkoxy), phenoxy (optionallysubstituted with from 1 to 3 substituents each independently selectedfrom halogen, C₁-C₄alkyl and C₁-C₄alkoxy) or —CO₂(C₁-C₄alkyl).

Compounds of Group B also include those (Group B3) wherein R2, R4, R5and R6 are all H and R3 is C₁-C₄alkyl (optionally substituted with from1 to 7 halogen atoms), C₁-C₄alkyl-S(O)_(x)— wherein x is 0,1 or 2(optionally substituted with from 1 to 7 halogen atoms), C₁-C₄alkoxy(optionally substituted with from 1 to 7 halogen atoms), cyano, halogen,phenyl (optionally substituted with from 1 to 3 substituents eachindependently selected from halogen, C₁-C₄alkyl and C₁-C₄alkoxy),phenoxy (optionally substituted with from 1 to 3 substituents eachindependently selected from halogen, C₁-C₄alkyl and C₁-C₄alkoxy) or—CO₂(C₁-C₄alkyl).

Compounds of Group B also include those (Group B4) wherein R2, R3, R5and R6 are all H and R4 is C₁-C₄alkyl (optionally substituted with from1 to 7 halogen atoms), C₁-C₄alkyl-S(O)_(x)— wherein x is 0,1 or 2(optionally substituted with from 1 to 7 halogen atoms), C₁-C₄alkoxy(optionally substituted with from 1 to 7 halogen atoms), cyano, halogen,phenyl (optionally substituted with from 1 to 3 substituents eachindependently selected from halogen, C₁-C₄alkyl and C₁-C₄alkoxy),phenoxy (optionally substituted with from 1 to 3 substituents eachindependently selected from halogen, C₁-C₄alkyl and C₁-C₄alkoxy) or—CO₂(C₁-C₄alkyl).

A further embodiment provides a group (Group C) of compounds of formula(IA) above, wherein two of R2, R3, R4, R5 and R6 are not H and theothers are H.

Compounds of Group C include those (Group C2,3) wherein R4, R5 and R6are all H; R2 is C₁-C₄alkyl (optionally substituted with from 1 to 7halogen atoms), C₁-C₄alkyl-S(O)_(x)— wherein x is 0,1 or 2 (optionallysubstituted with from 1 to 7 halogen atoms), C₁-C₄alkoxy (optionallysubstituted with from 1 to 7 halogen atoms), cyano, halogen, phenyl(optionally substituted with from 1 to 3 substituents each independentlyselected from halogen, C₁-C₄alkyl and C₁-C₄alkoxy), phenoxy (optionallysubstituted with from 1 to 3 substituents each independently selectedfrom halogen, C₁-C₄alkyl and C₁-C₄alkoxy) or —CO₂(C₁-C₄alkyl), ortogether with R3 forms a further benzene ring (optionally substitutedwith from 1 to 3 substituents each independently selected from halogen,C₁-C₄alkyl and C₁-C₄alkoxy); and R3 is C₁-C₄alkyl (optionallysubstituted with from 1 to 7 halogen atoms), C₁-C₄alkyl-S(O)_(x)—wherein x is 0,1 or 2 (optionally substituted with from 1 to 7 halogenatoms), C₁-C₄alkoxy (optionally substituted with from 1 to 7 halogenatoms), cyano, halogen, phenyl (optionally substituted with from 1 to 3substituents each independently selected from halogen, C₁-C₄alkyl andC₁-C₄alkoxy), phenoxy (optionally substituted with from 1 to 3substituents each independently selected from halogen, C₁-C₄alkyl andC₁-C₄alkoxy) or —CO₂(C₁-C₄alkyl), or together with R2 forms a furtherbenzene ring (optionally substituted with from 1 to 3 substituents eachindependently selected from halogen, C₁-C₄alkyl and C₁-C₄alkoxy).

Compounds of Group C also include those (Group C2,4) wherein R3, R5 andR6 are all H; R2 is C₁-C₄alkyl (optionally substituted with from 1 to 7halogen atoms), C₁-C₄alkyl-S(O)_(x)— wherein x is 0,1 or 2 (optionallysubstituted with from 1 to 7 halogen atoms), C₁-C₄alkoxy (optionallysubstituted with from 1 to 7 halogen atoms), cyano, halogen, phenyl(optionally substituted with from 1 to 3 substituents each independentlyselected from halogen, C₁-C₄alkyl and C₁-C₄alkoxy), phenoxy (optionallysubstituted with from 1 to 3 substituents each independently selectedfrom halogen, C₁-C₄alkyl and C₁-C₄alkoxy) or —CO₂(C₁-C₄alkyl); and R4 isC₁-C₄alkyl (optionally substituted with from 1 to 7 halogen atoms),C₁-C₄alkyl-S(O)X— wherein x is 0,1 or 2 (optionally substituted withfrom 1 to 7 halogen atoms), C₁-C₄alkoxy (optionally substituted withfrom 1 to 7 halogen atoms), cyano, halogen, phenyl (optionallysubstituted with from 1 to 3 substituents each independently selectedfrom halogen, C₁-C₄alkyl and C₁-C₄alkoxy), phenoxy (optionallysubstituted with from 1 to 3 substituents each independently selectedfrom halogen, C₁-C₄alkyl and C₁-C₄alkoxy) or —CO₂(C₁-C₄alkyl).

Compounds of Group C also include those (Group C2,5) wherein R3, R4 andR6 are all H; R2 is C₁-C₄alkyl (optionally substituted with from 1 to 7halogen atoms), C₁-C₄alkyl-S(O)_(x)— wherein x is 0,1 or 2 (optionallysubstituted with from 1 to 7 halogen atoms), C₁-C₄alkoxy (optionallysubstituted with from 1 to 7 halogen atoms), cyano, halogen, phenyl(optionally substituted with from 1 to 3 substituents each independentlyselected from halogen, C₁-C₄alkyl and C₁-C₄alkoxy), phenoxy (optionallysubstituted with from 1 to 3 substituents each independently selectedfrom halogen, C₁-C₄alkyl and C₁-C₄alkoxy) or —CO₂(C₁-C₄alkyl); and R5 isC₁-C₄alkyl (optionally substituted with from 1 to 7 halogen atoms),C₁-C₄alkoxy (optionally substituted with from 1 to 7 halogen atoms) orhalogen.

Compounds of Group C also include those (Group C2,6) wherein R3, R4 andR5 are all H; R2 is C₁-C₄alkyl (optionally substituted with from 1 to 7halogen atoms), C₁-C₄alkyl-S(O)_(x)— wherein x is 0,1 or 2 (optionallysubstituted with from 1 to 7 halogen atoms), C₁-C₄alkoxy (optionallysubstituted with from 1 to 7 halogen atoms), cyano, halogen, phenyl(optionally substituted with from 1 to 3 substituents each independentlyselected from halogen, C₁-C₄alkyl and C₁-C₄alkoxy), phenoxy (optionallysubstituted with from 1 to 3 substituents each independently selectedfrom halogen, C₁-C₄alkyl and C₁-C₄alkoxy) or —CO₂(C₁-C₄alkyl); and R6 isC₁-C₄alkyl (optionally substituted with from 1 to 7 halogen atoms),C₁-C₄alkoxy (optionally substituted with from 1 to 7 halogen atoms) orhalogen.

Compounds of Group C also include those (Group C3,4) wherein R2, R5 andR6 are all H; R3 is C₁-C₄alkyl (optionally substituted with from 1 to 7halogen atoms), C₁-C₄alkyl-S(O)_(x)— wherein x is 0,1 or 2 (optionallysubstituted with from 1 to 7 halogen atoms), C₁-C₄alkoxy (optionallysubstituted with from 1 to 7 halogen atoms), cyano, halogen, phenyl(optionally substituted with from 1 to 3 substituents each independentlyselected from halogen, C₁-C₄alkyl and C₁-C₄alkoxy), phenoxy (optionallysubstituted with from 1 to 3 substituents each independently selectedfrom halogen, C₁-C₄alkyl and C₁-C₄alkoxy) or —CO₂(C₁-C₄alkyl), ortogether with R4 forms a further benzene ring (optionally substitutedwith from 1 to 3 substituents each independently selected from halogen,C₁-C₄alkyl and C₁-C₄alkoxy); and R4 is C₁-C₄alkyl (optionallysubstituted with from 1 to 7 halogen atoms), C₁-C₄alkyl-S(O)_(x)—wherein x is 0,1 or 2 (optionally substituted with from 1 to 7 halogenatoms), C₁-C₄alkoxy (optionally substituted with from 1 to 7 halogenatoms), cyano, halogen, phenyl (optionally substituted with from 1 to 3substituents each independently selected from halogen, C₁-C₄alkyl andC₁-C₄alkoxy), phenoxy (optionally substituted with from 1 to 3substituents each independently selected from halogen, C₁-C₄alkyl andC₁-C₄alkoxy) or —CO₂(C₁-C₄alkyl), or together with R3 forms a furtherbenzene ring (optionally substituted with from 1 to 3 substituents eachindependently selected from halogen, C₁-C₄alkyl and C₁-C₄alkoxy).

Compounds of Group C also include those (Group C3,5) wherein R2, R4 andR6 are all H; R3 is C₁-C₄alkyl (optionally substituted with from 1 to 7halogen atoms), C₁-C₄alkyl-S(O)_(x)— wherein x is 0,1 or 2 (optionallysubstituted with from 1 to 7 halogen atoms), C₁-C₄alkoxy (optionallysubstituted with from 1 to 7 halogen atoms), cyano, halogen, phenyl(optionally substituted with from 1 to 3 substituents each independentlyselected from halogen, C₁-C₄alkyl and C₁-C₄alkoxy), phenoxy (optionallysubstituted with from 1 to 3 substituents each independently selectedfrom halogen, C₁-C₄alkyl and C₁-C₄alkoxy) or —CO₂(C₁-C₄alkyl); and R5 isC₁-C₄alkyl (optionally substituted with from 1 to 7 halogen atoms),C₁-C₄alkoxy (optionally substituted with from 1 to 7 halogen atoms) orhalogen.

For compounds of Formula (IA) falling within any one of groups A, B, B2,B3, B4, C, C2,3, C2,4, C2,5, C2,6, C3,4 and C3,5 described above, n ispreferably 1 or 2, more preferably 1.

For compounds of Formula (IA) falling within any one of groups A, B, B2,B3, B4, C, C2,3, C2,4, C2,5, C2,6, C3,4 and C3,5 described above, R7 ispreferably H or methyl, more preferably H.

For compounds of Formula (IA) falling within any one of groups A, B, B2,B3, B4, C, C2,3, C2,4, C2,5, C2,6, C3,4 and C3,5 described above, R8 ispreferably H.

For compounds of Formula (IA) falling within any one of groups A, B, B2,B3, B4, C, C2,3, C2,4, C2,5, C2,6, C3,4 and C3,5 described above, R9 ispreferably H or fluoro, more preferably H.

For compounds of Formula (IA) falling within any one of groups A, B, B2,B3, B4, C, C2,3, C2,4, C2,5, C2,6, C3,4 and C3,5 described above, R10 ispreferably H or fluoro, more preferably H.

For compounds of Formula (IA) falling within any one of groups A, B, B2,B3, B4, C, C2,3, C2,4, C2,5, C2,6, C3,4 and C3,5 described above, R¹ ispreferably a C₂-C₁₀alkyl group optionally substituted with from 1 to 7halogen substituents and/or with from 1 to 3 substituents eachindependently selected from hydroxy, cyano and C₁-C₄alkoxy.

For compounds of Formula (IA) falling within any one of groups A, B, B2,B3, B4, C, C2,3, C2,4, C2,5, C2,6, C3,4 and C3,5 described above, n ispreferably 1, R7, R8, R9 and R10 are preferably H and R¹ is preferably aC₂-C₁₀alkyl group optionally substituted with from 1 to 7 halogensubstituents and/or with from 1 to 3 substituents each independentlyselected from hydroxy, cyano and C₁-C₄alkoxy.

5. A compound of formula (IB)

wherein Rx is H; Ry is H or C₁-C₄ alkyl; each Rz is independently H orC₁-C₄ alkyl; X represents O; Y represents OH or OR; R is C₁-C₄ alkyl;Ar₁ is a phenyl ring or a 5- or 6-membered heteroaryl ring each of whichmay be substituted with 1, 2, 3, 4 or 5 substituents (depending upon thenumber of available substitution positions) each independently selectedfrom C₁-C₄ alkyl, O(C₁-C₄ alkyl), S(C₁-C₄ alkyl), halo, hydroxy,pyridyl, thiophenyl and phenyl optionally substituted with 1, 2, 3, 4 or5 substituents each independently selected from halo, C₁-C₄ alkyl, orO(C₁-C₄ alkyl); and Ar₂ is a phenyl ring or a 5- or 6-memberedheteroaryl ring each of which may be substituted with 1, 2, 3, 4 or 5substituents (depending upon the number of available substitutionpositions) each independently selected from C₁-C₄ alkyl, O(C₁-C₄ alkyl)and halo; wherein each above-mentioned C₁-C₄ alkyl group is optionallysubstituted with one or more halo atoms; or a pharmaceuticallyacceptable salt thereof.

Preferred compounds of formula (IB) above are those wherein Ar₁ isphenyl, pyridyl, pyrimidyl, thiazolyl, isothiazolyl, oxazolyl,isoxazolyl, thiophenyl, furanyl, imidazolyl, triazolyl, oxadiazolyl orthiadiazolyl, each of which may be substituted with 1, 2, 3, 4 or 5substituents (depending upon the number of available substitutionpositions) each independently selected from C₁-C₄ alkyl, O(C₁-C₄ alkyl),S(C₁-C₄ alkyl), halo, hydroxy, pyridyl, thiophenyl and phenyl optionallysubstituted with 1, 2, 3, 4 or 5 substituents each independentlyselected from halo, C₁-C₄ alkyl, or O(C₁-C₄ alkyl); and Ar₂ is phenyl,pyridyl, pyrimidyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl,thiophenyl, furanyl, imidazolyl or triazolyl each of which may besubstituted with 1, 2, 3, 4 or 5 substituents (depending upon the numberof available substitution positions) each independently selected fromC₁-C₄ alkyl, O(C₁-C₄ alkyl) and halo; wherein each above-mentioned C₁-C₄alkyl group is optionally substituted with one or more halo atoms.

For the compounds of formula (IB) above, it is preferred that Ar₁ is aphenyl ring or a 5- or 6-membered heteroaryl ring substituted with 1, 2,3, 4 or 5 substituents, more preferably with 1 or 2 substituents.

For the compounds of formula (IB) above, when Ar₁ is a substitutedphenyl ring or a substituted 5- or 6-membered heteroaryl ring, it ispreferred that not more than one of those substituents is a pyridyl,thiophenyl or optionally substituted phenyl group.

Preferred compounds of formula (IB) above are those wherein Ar₁ includesa substituent attached at the 2-position. That is, the substituent isattached to the atom adjacent to that which forms the point ofattachment of Ar₁ to the methylene group connecting Ar₁ to the rest ofthe molecule. For example, when Ar₁ is phenyl, it is preferablyortho-substituted.

Further preferred compounds of formula (IB) above are those wherein Rxis H; Ry is H or C₁-C₄ alkyl; each Rz is independently H or C₁-C₄ alkyl;X represents O; Y represents OH or OR; R is C₁-C₄ alkyl; and Ar₁ and Ar₂are each independently selected from the group consisting of phenyl, andsubstituted phenyl; and pharmaceutically acceptable salts thereof. Inthis further preferred embodiment, the group Ar₁ may be substituted orunsubstituted phenyl. For example, Ar₁ may be unsubstituted phenyl or,preferably phenyl substituted with 1, 2, 3, 4 or 5 substituents,preferably with 1 or 2, for example 1, substituent. When disubstituted,the substituted phenyl group is preferably substituted at the 2- and 5-positions. When monosubstituted, the substituted phenyl group ispreferably substituted in the 2- position. Suitable substituents includeC₁-C₄ alkyl, O(C₁-C₄ alkyl), S(C₁-C₄ alkyl), halo, and phenyl,optionally substituted with, for example, halo, C₁-C₄ alkyl, or O(C₁-C₄alkyl). In this further preferred embodiment, the group Ar₂ may besubstituted or unsubstituted phenyl. For example, Ar₂ may be phenylsubstituted with 1, 2, 3, 4 or 5 substituents, preferably with 1substituent. Suitable substituents include C₁-C₄ alkyl, O(C₁-C₄ alkyl),and especially, halo.

“C₁-C₄ alkyl” as used in respect of compounds of formula (IB) includesstraight and branched chain alkyl groups of 1, 2, 3 or 4 carbon atoms,and may be unsubstituted or substituted. C₁-C₂ alkyl groups arepreferred. Suitable substituents include halo, especially Cl and/or F.Thus the term “C₁-C₄ alkyl” includes haloalkyl. A particularly preferredsubstituted C₁-C₄ alkyl group is trifluoromethyl. Similar terms definingdifferent numbers of C atoms (e.g. “C₁-C₃ alkyl”) take an analogousmeaning. When Ry is C₁-C₄ alkyl it is preferably unsubstituted. When Rzis C₁-C₄ alkyl it is preferably unsubstituted. When R is C₁-C₄ alkyl itis preferably unsubstituted.

“5-membered heteroaryl ring” as used in respect of compounds of formula(IB) means a 5-membered aromatic ring including at least one heteroatomindependently selected from N, O and S. Preferably there are not morethan three heteroatoms in total in the ring. More preferably there arenot more than two heteroatoms in total in the ring. More preferablythere is not more than one heteroatom in total in the ring. The termincludes, for example, the groups thiazolyl, isothiazolyl, oxazolyl,isoxazolyl, thiophenyl, furanyl, pyrrolyl, imidazolyl, triazolyl,oxadiazolyl and thiadiazolyl.

“6-membered heteroaryl ring” as used in respect of compounds of formula(IB) means a 6-membered aromatic ring including at least one heteroatomindependently selected from N, O and S. Preferably there are not morethan three heteroatoms in total in the ring. More preferably there arenot more than two heteroatoms in total in the ring. More preferablythere is not more than one heteroatom in total in the ring. The termincludes, for example, the groups pyridyl, pyrimidyl, pyrazinyl,pyridazinyl and triazinyl.

“Halo” as used in respect of compounds of formula (lB) includes F, Cl,Br and I, and is preferably F or Cl.

“Pyridyl” as used in respect of compounds of formula (IB) includes2-pyridyl, 3-pyridyl and 4-pyridyl.

“Pyrimidyl” as used in respect of compounds of formula (IB) includes2-pyrimidyl, 4-pyrimidyl and 5-pyrimidyl.

“Pyridazinyl” as used in respect of compounds of formula (IB) includes3-pyridazinyl and 4-pyridazinyl.

“Pyrazinyl” as used in respect of compounds of formula (IB) includes2-pyrazinyl and 3-pyrazinyl.

“Triazinyl” as used in respect of compounds of formula (IB) includes2-(1,3,5-triazinyl), 3-, 5- and 6-(1,2,4-triazinyl) and 4- and5-(1,2,3-triazinyl).

“Thiazolyl” as used in respect of compounds of formula (IB) includes2-thiazolyl, 4-thiazolyl and 5-thiazolyl.

“Isothiazolyl” as used in respect of compounds of formula (IB) includes3-isothiazolyl, 4-isothiazolyl, and 5-isothiazolyl.

“Oxazolyl” as used in respect of compounds of formula (IB) includes2-oxazolyl, 4-oxazolyl and 5-oxazolyl.

“Isoxazolyl” as used in respect of compounds of formula (IB) includes3-isoxazolyl, 4-isoxazolyl, and 5-isoxazolyl.

“Thiophenyl” as used in respect of compounds of formula (IB) includes2-thiophenyl and 3-thiophenyl.

“Furanyl” as used in respect of compounds of formula (IB) includes2-furanyl and 3-furanyl.

“Pyrrolyl” as used in respect of compounds of formula (IB) includes2-pyrrolyl and 3-pyrrolyl.

“Imidazolyl” as used in respect of compounds of formula (IB) includes2-imidazolyl and 4-imidazolyl.

“Triazolyl” as used in respect of compounds of formula (IB) includes1-triazolyl, 4-triazolyl and 5-triazolyl.

“Oxadiazolyl” as used in respect of compounds of formula (IB) includes4- and 5-(1,2,3-oxadiazolyl), 3- and 5—(1,2,4-oxadiazolyl),3-(1,2,5-oxadiazolyl), 2-(1,3,4-oxadiazolyl).

“Thiadiazolyl” as used in respect of compounds of formula (1B) includes4- and 5-(1,2,3-thiadiazolyl), 3- and 5-(1,2,4-thiadiazolyl),3-(1,2,5-thiadiazolyl), 2-(1,3,4-thiadiazolyl).

For the compounds of formula (IB) above, Ry is preferably H or Me. Morepreferably Ry is H.

For the compounds of formula (IB) above, each Rz is preferably H or Mewith 0, 1, 2 or 3 of Rz being Me. More preferably only 1 Rz is Me. Mostpreferably all Rz are H.

For the compounds of formula (IB) above, Y is preferably OH or OMe. Morepreferably, Y is OH.

For the compounds of formula (IB) above, it is preferred that Ry and allRz are H and Y is OH.

For the compounds of formula (IB) above, the preferred stereochemistryis shown below:

A preferred group of compounds of formula (IB) is represented by theformula (IIB)

wherein R₁ and R₂ are each independently selected from H, C₁-C₄ alkyl,O(C₁-C₄ alkyl), S(C₁-C₄ alkyl), halo and phenyl; and R₃ is selected fromH, C₁-C₄ alkyl and halo; and pharmaceutically acceptable salts thereof.

For the compounds of formula (IB) or (IIB) above, R₁ is preferably C₁-C₃alkyl (especially trifluoromethyl), O(C₁-C₃ alkyl) (especially methoxyor trifluoromethoxy), F or phenyl (Ph). R₂ is preferably H. R₂ is alsopreferably F. R₃ is preferably H.

Especially preferred compounds of formula (IB) are1-morpholin-2-yl-1-phenyl-2-(2-trifluoromethoxy-phenyl)-ethanol and2-(5-fluoro-2-methoxy-phenyl)-1-morpholin-2-yl-1-phenyl-ethanol. Forboth of these compounds the (S,R) stereoisomer is preferred. For both ofthese compounds the preferred salt form is the hydrochloride salt.

6. A compound of formula (IC)

wherein: A is S or O; R is H; Ar is a phenyl group optionallysubstituted with 1, 2, 3, 4 or 5 substituents each independentlyselected from C₁-C₄ alkyl, O(C₁-C₄ alkyl), S(C₁-C₄ alkyl), halo,hydroxy, CO₂(C₁-C₄ alkyl), pyridyl, thiophenyl and phenyl optionallysubstituted with 1, 2, 3, 4 or 5 substituents each independentlyselected from halo, C₁-C₄ alkyl, or O(C₁-C₄ alkyl); X is a phenyl groupoptionally substituted with 1, 2, 3, 4 or 5 substituents eachindependently selected from halo, C₁-C₄ alkyl, or O(C₁-C₄ alkyl); aC₁-C₄ alkyl group; a C₃-C₆ cycloalkyl group or a CH₂(C₃-C₆ cycloalkyl)group; R¹ is H or C₁-C₄ alkyl; each R¹ is independently H or C₁-C₄alkyl; wherein each above-mentioned C₁-C₄ alkyl group is optionallysubstituted with one or more halo atoms; or a pharmaceuticallyacceptable salt thereof; with the proviso that, when A is O, X is aC₁-C₄ alkyl group, a C₃-C₆ cycloalkyl group or a CH₂(C₃-C₆ cycloalkyl)group.

For the compounds of formula (IC) above, it is preferred that A is S.

For the compounds of formula (IC) above, it is preferred that Ar isphenyl substituted with 1, 2, 3, 4 or 5 substituents, more preferablywith 1 or 2 substituents. When Ar is a substituted phenyl, it ispreferred that not more than one of those substituents is a pyridyl,thiophenyl or optionally substituted phenyl group.

Preferred compounds of formula (IC) above are those wherein Ar isortho-substituted.

Further preferred compounds of formula (IC) above are those of formula(ICa)

wherein: R is H; Ar is a phenyl group; X is a phenyl SSgroup; R¹ is H orC₁-C₄ alkyl; each R¹ is independently H or C₁-C₄ alkyl; andpharmaceutically acceptable salts thereof. For these further preferredcompounds, the group Ar may be substituted or unsubstituted phenyl. Forexample, Ar may be unsubstituted phenyl or, preferably phenylsubstituted with 1, 2, 3, 4 or 5 substituents, preferably with 1 or 2,for example 1, substituent. When disubstituted, the substituted phenylgroup is preferably substituted at the 2- and 5-positions Whenmonosubstituted, the substituted phenyl group is preferably substitutedin the 2- position. Suitable substituents include C₁-C₄ alkyl, O(C₁-C₄alkyl), S(C₁-C₄alkyl), halo, and phenyl optionally substituted with, forexample, halo, C₁-C₄ alkyl, or O(C₁-C₄ alkyl). For these furtherpreferred compounds, the group X may be substituted or unsubstitutedphenyl. For example, X may be phenyl substituted with 1, 2, 3, 4 or 5substituents, preferably with 1 substituent. Suitable substituentsinclude C₁-C₄ alkyl, O(C₁-C₄ alkyl), and halo.

“C₁-C₄ alkyl” as used in respect of compounds of formula (IC) includesstraight and branched chain alkyl groups of 1, 2, 3 or 4 carbon atoms,and may be unsubstituted or substituted. C₁-C₂ alkyl groups arepreferred. Suitable substituents include halo. Thus the term “C₁-C₄alkyl” includes haloalkyl. Similar termns defining different numbers ofC atoms (e.g. “C₁-C₃ alkyl”) take an analogous meaning. When R¹ is C₁-C₄alkyl it is preferably unsubstituted. When R¹ is C₁-C₄ alkyl it ispreferably unsubstituted.

“C₃-C₆ cycloalkyl” as used in respect of compounds of formula (IC)includes cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

“Halo” as used in respect of compounds of formula (IC) includes F, Cl,Br and I, and is preferably F or Cl.

“Pyridyl” as used in respect of compounds of formula (IC) includes2-pyridyl, 3-pyridyl and 4-pyridyl.

“Thiophenyl” as used in respect of compounds of formula (IC) includes2-thiophenyl and 3-thiophenyl.

For the compounds of formula (IC) above, R¹ is preferably H or Me. Morepreferably R¹ is H.

For the compounds of formula (IC) above, each R¹ is preferably H or Mewith 0, 1, 2 or 3 of R¹ being Me. More preferably only 1 R¹ is Me. Mostpreferably all R¹ are H.

For the compounds of formula (IC) above, it is preferred that R¹ and allR¹ are H.

A particularly preferred substituted C₁-C₄ alkyl group for the group Aris trifluoromethyl.

A preferred group of compounds of formula (IC) is represented by theformula (IIC);

wherein R₂ and R₃ are each independently selected from H, C₁-C₄ alkyl,O(C₁-C₄ alkyl), S(C₁-C₄ alkyl), halo and phenyl; and R₄ is selected fromH and C₁-C₄ alkyl; and pharmaceutically acceptable salts thereof. R₂ ispreferably C₁-C₃ alkyl (especially trifluoromethyl), O(C₁-C₃ alkyl)(especially methoxy or trifluoromethoxy), F or Ph. R₃ is preferably H.R₃ is also preferably F. R₄ is preferably H.

7. A compound of formula (ID)

wherein —X— is —C(R⁴R⁵)—, —O— or —S—; n is 2 or 3; R¹ is H or C₁-C₄alkyl; R³ is H, halo, C₁-C₄ alkyl, O(C₁-C₄ alkyl), nitrile, phenyl orsubstituted phenyl; R⁴ and R⁵ are each independently selected from H orC₁-C₄ alkyl; Ar— is selected from the group consisting of

in which R^(2a) is H, halo, methyl or ethyl; R^(2b) is H, halo ormethyl; R^(2c) is H, halo, methyl, trifluoromethyl, nitrile, or methoxy;R^(2d) is H, halo, methyl or ethyl; R^(2e) is H, halo, methyl,trifluoromethyl, nitrile, or methoxy; R^(2f) is H, or fluoro; —Y— is—O—, —S— or —N(R⁶)—; and R⁶ is H or methyl and pharmaceuticallyacceptable salts thereof.

The term “C₁-C₄ alkyl” as used in respect of compounds of formula (ID)includes straight and branched chain alkyl groups of 1, 2, 3 or 4 carbonatoms. Thus the term “C₁-C₄ alkyl” includes methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl. C₁-C₂ alkylgroups are preferred. A particularly preferred C₁-C₄ alkyl group ismethyl or ethyl.

The term “halo” as used in respect of compounds of formula (ID) includesF, Cl, Br and I, and is preferably F or Cl.

The term “substituted phenyl” as used in respect of compounds of formula(ID) means phenyl substituted with 1, 2, 3, 4 or 5 substituents,preferably with 1 or 2, for example 1, substituent. Suitablesubstituents include C₁-C₄ alkyl, O(C₁-C₄ alkyl), S(C₁-C₄alkyl), halo,and phenyl optionally substituted with, for example, C₁-C₄ alkyl,O(C₁-C₄alkyl), S(C₁-C₄ alkyl), or halo.

The terms “O(C₁-C₄ alkyl)” or “S(C₁-C₄ alkyl)” as used in respect ofcompounds of formula (ID) mean a C₁-C₄ alkyl group as defined abovelinked to the point of substitution via an oxygen or a sulphur atom. AnO(C₁-C₄ alkyl) or S(C₁-C₄ alkyl) group includes for example methoxy,ethoxy, thiomethyl or thioethyl.

Preferred compounds of formula (ID) are represented by the formula (IDa)

wherein —X—, n, R¹, R³ and Ar have the values as defined for formula(ID) above.

Compounds of formula (ID) or (IDa) wherein —X— is —C(R⁴R⁵)— arepreferred. Even more preferred are compounds of formula (ID) or (IDa)wherein —X— is —C(R⁴R⁵)— and R⁴ and R⁵ are both H or R⁴ and R⁵ are boththe same C₁-C₄ alkyl.

Compounds of formula (ID) or (IDa) wherein Ar is (i) are also preferred.Preferably Ar is (i) and R^(2c) is H. Even more preferred are compoundsof formula (ID) or (IDa) wherein Ar is (i), R^(2c) is H, and (a) R^(2a)is H or methyl, R^(2b) is H and R^(2f) is H or (b) R^(2a) is H, R^(2b)is halo, preferably fluoro or chloro and R^(2f) is H or fluoro.

Another group of preferred compounds of formula (ID) or (IDa) arecompounds wherein Ar is (ii) and —Y— is —S—. More preferably Ar is2-thiophenyl or 3-thiophenyl.

A further preferred group of compounds of formula (ID) is represented bythe formula (IID)

wherein n is 2 or 3; R¹ is H or C₁-C₄ alkyl; R³ is H, halo, phenyl orsubstituted phenyl; R^(2a) is H, halo, methyl or ethyl; R^(2b) is H,halo or methyl; and pharmaceutically acceptable salts thereof.

Preferred compounds of formulae (ID), (IDa) and (IID) are those whereinn is 3, or wherein R¹ is H, methyl, ethyl or n-propyl, or wherein R³ isH or halo.

8. A compound of formula (IE)

wherein R¹ is C₁-C₆ alkyl (optionally substituted with 1, 2 or 3 halosubstituents and/or with 1 substituent selected from —S—(C₁-C₃ alkyl),—O—(C₁-C₃ alkyl) (optionally substituted with 1, 2 or 3 F atoms),—O—(C₃-C₆ cycloalkyl), —SO₂—(C₁-C₃ alkyl), —CN, —COO—(C₁-C₂ alkyl) and—OH); C₂-C₆ alkenyl; —(CH₂)_(q)—Ar₂; or a group of formula (i) or (ii)

R², R³ and R⁴ are each independently selected from hydrogen or C₁-C₂alkyl; R⁵, R⁶, R⁷ and R⁸ are at each occurrence independently selectedfrom hydrogen or C₁-C₂ alkyl; —X— is a bond, —CH₂—, —CH═CH—, —O—, —S—,or —SO₂—; —Y— is a bond, —CH₂— or —O—; -Z is hydrogen, —OH or —O—(C₁-C₃alkyl); p is 0, 1 or 2; q is 0, 1 or 2; r is 0 or 1; s is 0, 1, 2 or 3;t is 0, 1, 2 or 3; Ar₁ is phenyl, pyridyl, thiazolyl, benzothiophenyl ornaphthyl; wherein said phenyl, pyridyl or thiazolyl group may besubstituted with 1, 2 or 3 substituents each independently selected fromhalo, cyano, C₁-C₄ alkyl (optionally substituted with 1, 2 or 3 Fatoms), —O—(C₁-C₄ alkyl) (optionally substituted with 1, 2 or 3 F atoms)and —S—(C₁-C₄ alkyl) (optionally substituted with 1, 2 or 3 F atoms)and/or with 1 substituent selected from pyridyl, pyrazole, phenyl(optionally substituted with 1, 2 or 3 halo substituents) and phenoxy(optionally substituted with 1, 2 or 3 halo substituents); and whereinsaid benzothiophenyl or naphthyl group may be optionally substitutedwith 1, 2 or 3 substituents each independently selected from halo,cyano, C₁-C₄ alkyl (optionally substituted with 1, 2 or 3 F atoms),—O—(C₁-C₄ alkyl) (optionally substituted with 1, 2 or 3 F atoms), and—S—(C₁-C₄ alkyl) (optionally substituted with 1, 2 or 3 F atoms); Ar₂ isnaphthyl, pyridyl, thiazolyl, furyl, thiophenyl, benzothiophenyl, orphenyl, wherein said naphthyl, pyridyl, thiazolyl, furyl, thiophenyl,benzothiophenyl, or phenyl may be substituted with 1, 2 or 3substituents each independently selected from halo, C₁-C₄ alkyl(optionally substituted with 1, 2 or 3 F atoms) and —O—(C₁-C₄ alkyl)(optionally substituted with 1, 2 or 3 F atoms); and pharmaceuticallyacceptable salts thereof; provided that (a) the cyclic portion of thegroup of formula (i) must contain at least three carbon atoms and notmore than seven ring atoms; (b) when —X— is —CH═CH—, then the cyclicportion of the group of formula (i) must contain at least five carbonatoms; and (c) when -Z is —OH or —O—(C₁-C₃ alkyl), then —X— is —CH₂—;(d) when —Y— is —O— then p cannot be 0; and (e) the compound3-[(phenylmethyl)-(3S)-3-pyrrolidinylamino]-propanenitrile is excluded.

With respect to formula (IE) the term “C₁-C₆ alkyl” means a monovalentunsubstituted saturated straight-chain or branched-chain hydrocarbonradical having from 1 to 6 carbon atoms.

With respect to formula (IE) the term “C₂-C₆ alkenyl” means a monovalentunsubstituted unsaturated straight-chain or branched-chain hydrocarbonradical having from 2 to 6 carbon atoms and containing at least onecarbon-carbon double bond.

With respect to formula (IE) the term “C₃-C₆ cycloalkyl” means amonovalent unsubstituted saturated cyclic hydrocarbon radical havingfrom 3 to 6 carbon atoms.

With respect to formula (IE) the term “C₁-C₆ alkylene” means a divalentunsubstituted saturated straight-chain or branched-chain hydrocarbonradical having from 1 to 6 carbon atoms.

With respect to formula (IE) the term “halo” or “halogen” means F, Cl,Br or I.

With respect to formula (IE) the term “C₁-C₄ difluoroalkyl” means amonovalent unsubstituted saturated straight-chain or branched-chainhydrocarbon radical having from 1 to 4 carbon atoms wherein two hydrogenatoms are substituted with two fluoro atoms. Preferably the two fluoroatoms are attached to the same carbon atom.

With respect to formula (IE) the term “C₁-C₄ trifluoroalkyl” means amonovalent unsubstituted saturated straight-chain or branched-chainhydrocarbon radical having from 1 to 4 carbon atoms wherein threehydrogen atoms are substituted with three fluoro atoms. Preferably thethree fluoro atoms are attached to the same carbon atom.

With respect to formula (IE) the term “phenoxy” means a monovalentunsubstituted phenyl radical linked to the point of substitution by an Oatom.

With respect to formula (IE) the term “pyridyl” includes 2-pyridyl,3-pyridyl and 4-pyridyl.

With respect to formula (IE) the term “furyl” includes 2-furyl and3-furyl. 2-furyl is preferred.

With respect to formula (IE) the term “thiophenyl” includes 2-thiophenyland 3-thiophenyl.

With respect to formula (IE) the term “thiazolyl” includes 2-thiazolyl,4-thiazolyl and 5-thiazolyl.

With respect to formula (IE) the term “pyrazole” includes 1-pyrazole,3-pyrazole and 4-pyrazole. 1-pyrazole is preferred.

With respect to formula (IE) the term “benzothiophenyl” includes2-benzo[b]thiophenyl, 3-benzo[b]thiophenyl, 4-benzo[b]thiophenyl,5-benzo[b]thiophenyl, 6-benzo[b]thiophenyl and 7-benzo[b]thiopbenyl.

With respect to formula (IE) the term “naphthyl” includes 1-naphthyl,and 2-naphthyl. 1-naphthyl is preferred.

With respect to formula (IE), similar terms specifying different numbersof C atoms take an analogous meaning. For example the terms “C₁-C₄alkyl” and “C₁-C₃ alkyl” mean a monovalent unsubstituted saturatedstraight-chain or branched-chain hydrocarbon radical having from 1 to 4and 1 to 3 carbon atoms respectively. The term “C₁-C₄ alkyl” includesmethyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, andtert-butyl. The term “C₁-C₃ alkyl” includes methyl, ethyl, n-propyl andiso-propyl.

With respect to formula (IE) it will be appreciated that when s is 2 or3, then each R⁵ and/or each R⁶ can be different. In the same way when tis 2 or 3, then each R⁷ and/or each R⁸ can be different.

Preferred compounds of formula (IE) are those wherein R¹ is C₁-C₆ alkyl,C₂-C₆ alkenyl, —(CH₂)_(m)—CF₃, —(CH₂)_(n)—S—(C₁-C₃ alkyl),—CH₂—COO—(C₁-C₂ alkyl), —(C₁-C₅ alkylene)-O—(C₁-C₃ alkyl), —(C₁-C₅alkylene)-O—(C₃-C₆ cycloalkyl), —(C₁-C₅ alkylene)-SO₂—(C₁-C₃ alkyl),—(C₁-C₅ alkylene)-OCF₃, —(C₁-C₆ alkylene)-OH, —(C₁-C₅ alkylene)-CN,—(CH₂)_(q)—Ar₂ or a group of formula (ia), (ib) or (ii)

R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, —X—, —Y—, p, q, r and s have the valuesdefined above; m is 1, 2 or 3; n is 1, 2 or 3; t is 2, 3 or 4; —Ar₁ isphenyl, pyridyl, thiazolyl or naphthyl; wherein said phenyl, pyridyl orthiazolyl group may be substituted with 1, 2 or 3 substituents eachindependently selected from halo, trifluoromethyl, cyano, C₁-C₄ alkyl,—O—(C₁-C₄ alkyl), —O—(C₁-C₄ difluoroalkyl), —O—(C₁-C₄ trifluoroalkyl),—S—(C₁-C₄ alkyl), —S—(C₁-C₂ trifluoroalkyl) and/or with 1 substituentselected from pyridyl, pyrazole, phenyl (optionally substituted with 1,2 or 3 halo substituents) and phenoxy (optionally substituted with 1, 2or 3 halo substituents); and wherein said naphthyl group may beoptionally substituted with 1, 2 or 3 substituents each independentlyselected from halo, trifluoromethyl, cyano, C₁-C₄ alkyl, —O—(C₁-C₄alkyl), —O—(C₁-C₄ difluoroalkyl), —O—(C₁-C₄ trifluoroalkyl), —S—(C₁-C₄alkyl), —S—(C₁-C₂ trifluoroalkyl); Ar₂ is naphthyl, pyridyl, thiazolyl,furyl, thiophenyl, benzothiophenyl, or phenyl, wherein said naphthyl,pyridyl, thiazolyl, furyl, thiophenyl, benzothiophenyl, or phenyl may besubstituted with 1, 2 or 3 substituents each independently selected fromhalo, C₁-C₄ alkyl, trifluoromethyl and —O— (C₁-C₄ alkyl); andpharmaceutically acceptable salts thereof.

Preferred compounds of formula (IE) are those wherein R² is hydrogen. Inanother preferred embodiment R³ and R⁴ are hydrogen. More preferably R²,R³ and R⁴ are hydrogen.

Preferred compounds of formula (IE) are those wherein each R⁵ and R⁶ ishydrogen. In another preferred embodiment each R⁷ and R⁸ is hydrogen.More preferably R⁵, R⁶, R⁷ and R⁸ are hydrogen.

Preferred compounds of formula (IE) are those wherein R¹ is C₁-C₆ alkyl.More preferably R¹ is n-propyl, 1-methylethyl, 2-methylpropyl,3,3-dimethylpropyl.

Preferred compounds of formula (IE) are those wherein R¹ is —(C₄-C₅alkylene)-OH. More preferably R¹ is 2,2-dimethyl-2-hydroxyethyl or3,3-dimethyl-3-hydroxypropyl.

Preferred compounds of formula (IE) are those wherein R¹ is a group offormula (i) and each R⁵ and R⁶ is hydrogen. More preferably each R⁵, R⁶,R⁷ and R⁸ is hydrogen.

Preferred compounds of formula (IE) are those wherein R¹ is a group offormula (ii) and each R⁵ and R⁶ is hydrogen. More preferably each R⁵,R⁶, R⁷ and R⁸ is hydrogen.

Preferred compounds of formula (IE) are those wherein R¹ is a group offormnula (i), r is O, s is 2, t is 2,-Z is hydrogen and —X— is —O—, —S—or —SO₂—. More preferably R¹ is a group of formula (i), r is 0, s is 2,t is 1 or 2, -Z is hydrogen and —X— is —O—.

Preferred compounds of formula (IE) are those wherein R¹ is a group offormula (i), r is 0, s is 1, 2 or 3, t is 1, -Z is hydrogen and —X— is—CH₂—.

Preferred compounds of formula (IE) are those wherein R¹ is a group offormula (i), r is 1, s is 0, 1, 2 or 3, t is 1, -Z is hydrogen and —X—is —CH₂—.

Preferred compounds of formula (IE) are those wherein R¹ is a group ofthe formula (ia). More preferably R¹ is a group of the formnula (ia) andeach R⁵, R⁶, R⁷and R⁸ is hydrogen.

Preferred compounds of formula (IE) are those wherein R¹ is a group ofthe formula (ib). More preferably R¹ is a group of the formula (ib), ris 1, t is 3, and each R⁷and R⁸ is hydrogen.

Preferred compounds of formula (IE) are those wherein R¹ is—(CH₂)_(m)—CF₃. More preferably R¹ is —(CH₂)_(m)—CF₃ and m is 1, 2, or3.

Preferred compounds of formula (IE) are those wherein R¹ is—(CH₂)_(n)—S—(C₁-C₃ alkyl). More preferably R¹ is —(CH₂)₃—S—CH₃.

Preferred compounds of formnula (IE) are those wherein R¹ is—CH₂—COO—(C₁-C₂ alkyl). More preferably R¹ is —CH₂—COOCH₃.

Preferred compounds of formula (IE) are those wherein R¹ is —(C₁-C₅alkylene)-O—(C₁-C₃ alkyl). More preferably R¹ is —(C₃-C₄ alkylene)-OCH₃.

Preferred compounds of formula (IE) are those wherein R¹ is —(C₁-C₅alkylene)-O—(C₃-C₆ cycloalkyl). More preferably R¹ is—CH₂-CH₂—O—cyclobutyl.

Preferred compounds of formula (IE) are those wherein R¹ is —(C₁-C₅alkylene)-SO₂—(C₁-C₃ alkyl).

Preferred compounds of formula (IE) are those wherein R¹ is —(C₁-C₅alkylene)-OCF₃. More preferably R¹ is —CH₂-CH₂—OCF₃.

Preferred compounds of formula (IE) are those wherein R¹ is —(C₁-C₅alkylene)-CN. More preferably R¹ is —(C₂-C₄ alkylene)-CN. Mostpreferably —CH₂—CH₂—CN or —CH₂—C(CH₃)₂—CN.

Preferred compounds of formula (IE) are those wherein R¹ is—(CH₂)_(q)—Ar₂, and q is 1. More preferably R¹ is —(CH₂)_(q)—Ar₂, q is 1and —Ar₂ is pyridyl, phenyl or phenyl substituted with 1, 2 or 3substituents each independently selected from halo, trifluoromethyl orC₁-C₄ alkyl.

Preferred compounds of formula (IE) are those wherein —Ar₁ is phenyl;phenyl substituted with 1, 2 or 3 substituents each independentlyselected from halo, trifluoromethyl and C₁-C₄ alkyl and/or with 1substituent selected from phenyl, phenyl substituted with 1, 2 or 3 halosubstituents, pyridyl, pyrazole, phenoxy and phenoxy substituted with 1,2 or 3 halo substituents; pyridyl; or pyridyl substituted with 1, 2 or 3substituents each independently selected from halo, trifluoromethyl andC₁-C₄ alkyl and/or with 1 substituent selected from phenyl and phenylsubstituted with 1, 2 or 3 halo substituents. More preferably —Ar₁ isphenyl or phenyl substituted with 1, 2 or 3 substituents eachindependently selected from halo, trifluoromethyl and C₁-C₄ alkyl and/orwith 1 substituent selected from phenyl, phenyl substituted with 1, 2 or3 halo substituents, pyridyl, pyrazole, phenoxy and phenoxy substitutedwith 1, 2 or 3 halo substituents. Most preferably —Ar₁ is phenylsubstituted with 1 or 2 substituents each independently selected fromhalo, trifluoromethyl and C₁-C₄ alkyl and/or with 1 substituent selectedfrom phenyl, phenyl substituted with 1, 2 or 3 halo substituents,pyridyl, pyrazole, phenoxy and phenoxy substituted with 1, 2 or 3 halosubstituents. Suitable —Ar₁ groups include, for example,2-methylthiophenyl, 2-methylphenyl, 2-fluorophenyl, 2-chlorophenyl,2-isopropoxyphenyl, 2-trifluoromethylphenyl, 2-difluoromethoxyphenyl,2-methoxyphenyl, 2-ethoxyphenyl, 2-(1,1′-biphenyl), 2-phenoxyphenyl,2-benzylphenyl, 3-trifluoromethoxyphenyl, 3-chlorophenyl,3-trifluoromethylphenyl, 3-methylphenyl, 3-trifluorothiomethoxyphenyl,3-methoxyphenyl, 4- trifluoromethylphenyl, 4-chlorophenyl,4-fluorophenyl, 3,5-dichlorophenyl, 3,5-dimethylphenyl,3-trifluoromethyl-5-fluorophenyl, 3,5-difluorophenyl,2,3-dichlorophenyl, 2,3-dimethylphenyl,2-chloro-3-trifluoromethylphenyl, 2-chloro-3-methylphenyl,2-methyl-3-chlorophenyl, 2,4-dichlorophenyl, 2,4-dimethyl,2,4-difluorophenyl, 2-chloro-4-fluorophenyl,2-trifluoromethyl-4-fluorophenyl, 2-fluoro-4-trifluoromethylphenyl,2-methyl4-chlorophenyl, 2-methoxy-4-fluorophenyl,2-trifluoromethyl-5-fluorophenyl, 2,5-dimethylphenyl,4-fluoro-[1,1′-biphenyl]-2-yl, 2-chloro-5-fluorophenyl,2-(trifluoromethyl)-6-fluorophenyl, 2-chloro-6-fluorophenyl,3,4-dichlorophenyl, and 3-chloro-4-fluorophenyl. In general when —Ar₁ isphenyl substituted with pyridyl, 3-pyridyl is preferred.

Preferred compounds of formula (IE) are those wherein —Ar₁ is pyridyl orpyridyl substituted with 1, 2 or 3 substituents each independentlyselected from halo, trifluoromethyl and C₁-C₄ alkyl and/or with 1substituent selected from phenyl and phenyl substituted with 1, 2 or 3halo substituents. More preferably —Ar₁ is pyridyl substituted with 1 or2 substituents each independently selected from halo, trifluoromethyland C₁-C₄ alkyl and/or with 1 substituent selected from phenyl andphenyl substituted with 1, 2 or 3 halo substituents. Suitable —Ar₁groups include, for example, 3-phenyl-2-pyridyl. In general when —Ar₁ isa substituted pyridyl, substituted 2-pyridyl is preferred.

9. A compound of formula (IF)

wherein

is a group of formnula (a) or (b)R¹ is C₁-C₆ alkyl (optionally substituted with 1, 2 or 3 halosubstituents and/or with 1 substituent selected from —S—(C₁-C₃ alkyl),—O—(C₁-C₃ alkyl) (optionally substituted with 1, 2 or 3 F atoms),—O—(C₃-C₆ cycloalkyl), —SO₂—(C₁-C₃ alkyl), —CN, —COO—(C₁-C₂ alkyl) and—OH); C₂-C₆ alkenyl; —(CH₂)_(q)—Ar₂; or a group of formula (i) or (ii)

R², R³ and R⁴ are each independently selected from hydrogen or C₁-C₂alkyl; R⁵, R⁶, R⁷ and R⁸ are at each occurrence independently selectedfrom hydrogen or C₁-C₂ alkyl; —X— is a bond, —CH₂—, —CH═CH—, —O—, —S-,or —SO₂—; —Y— is a bond, —CH₂— or —O—; -Z is hydrogen, —OH or —O—(C₁-C₃alkyl); p is 0, 1 or 2; q is 0, 1 or 2; r is 0 or 1; s is 0, 1, 2 or 3;t is 0, 1, 2 or 3; Ar₁ is phenyl, pyridyl, thiazolyl, benzothiophenyl ornaphthyl; wherein said phenyl, pyridyl or thiazolyl group may besubstituted with 1, 2 or 3 substituents each independently selected fromhalo, cyano, C₁-C₄ alkyl (optionally substituted with 1, 2 or 3 Fatoms), —O—(C₁-C₄ alkyl) (optionally substituted with 1, 2 or 3 F atoms)and —S—(C₁-C₄ alkyl) (optionally substituted with 1, 2 or 3 F atoms)and/or with 1 substituent selected from pyridyl, pyrazole, phenyl(optionally substituted with 1, 2 or 3 halo substituents), benzyl andphenoxy (optionally substituted with 1, 2 or 3 halo substituents); andwherein said benzothiophenyl or naphthyl group may be optionallysubstituted with 1, 2 or 3 substituents each independently selected fromhalo, cyano, C₁-C₄ alkyl (optionally substituted with 1, 2 or 3 Fatoms), —O—(C₁-C₄ alkyl) (optionally substituted with 1, 2 or 3 Fatoms), and —S—(C₁-C₄ alkyl) (optionally substituted with 1, 2 or 3 Fatoms); Ar₂ is naphthyl, pyridyl, thiazolyl, furyl, thiophenyl,benzothiophenyl, or phenyl, wherein said naphthyl, pyridyl, thiazolyl,furyl, thiophenyl, benzothiophenyl, or phenyl may be substituted with 1,2 or 3 substituents each independently selected from halo, C₁-C₄ alkyl(optionally substituted with 1, 2 or 3 F atoms) and —O—(C₁-C₄ alkyl)(optionally substituted with 1, 2 or 3 F atoms); or a pharmaceuticallyacceptable salt thereof; provided that (a) the cyclic portion of thegroup of formula (i) must contain at least three carbon atoms and notmore than seven ring atoms; (b) when —X— is —CH═CH—, then the cyclicportion of the group of formula (i) must contain at least five carbonatoms; and (c) when -Z is —OH or —O—(C₁-C₃ alkyl), then —X— is —CH₂—;and (d) when —Y— is —O— then p cannot be 0.

With respect to formula (IF) the term “C₁-C₆ alkyl” means a monovalentunsubstituted saturated straight-chain or branched-chain hydrocarbonradical having from 1 to 6 carbon atoms.

With respect to formula (IF) the term “C₂-C₆ alkenyl” means a monovalentunsubstituted unsaturated straight-chain or branched-chain hydrocarbonradical having from 2 to 6 carbon atoms and containing at least onecarbon-carbon double bond.

With respect to formula (IF) the term “C₃-C₆ cycloalkyl” means amonovalent unsubstituted saturated cyclic hydrocarbon radical havingfrom 3 to 6 carbon atoms.

With respect to formula (IF) the term “C₁-C₆ alkylene” means a divalentunsubstituted saturated straight-chain or branched-chain hydrocarbonradical having from 1 to 6 carbon atoms.

With respect to formula (IF) the term “halo” or “halogen” means F, Cl,Br or I.

With respect to formula (IF) the term “C₁-C₄ difluoroalkyl” means amonovalent unsubstituted saturated straight-chain or branched-chainhydrocarbon radical having from 1 to 4 carbon atoms wherein two hydrogenatoms are substituted with two fluoro atoms. Preferably the two fluoroatoms are attached to the same carbon atom.

With respect to formula (IF) the term “C₁-C₄ trifluoroalkyl” means amonovalent unsubstituted saturated straight-chain or branched-chainhydrocarbon radical having from 1 to 4 carbon atoms wherein threehydrogen atoms are substituted with three fluoro atoms. Preferably thethree fluoro atoms are attached to the same carbon atom.

With respect to formula (IF) the term “phenoxy” means a monovalentunsubstituted phenyl radical linked to the point of substitution by an Oatom.

With respect to formula (IF) the term “pyridyl” includes 2-pyridyl,3-pyridyl and 4-pyridyl.

With respect to formula (IF) the term “furyl” includes 2-furyl and3-furyl. 2-furyl is preferred.

With respect to formula (IF) the term “thiophenyl” includes 2-thiophenyland 3-thiophenyl.

With respect to formula (IF) the term “thiazolyl” includes 2-thiazolyl,4-thiazolyl and 5-thiazolyl.

With respect to formula (IF) the term “pyrazole” includes 1-pyrazole,3-pyrazole and 4-pyrazole. 1-pyrazole is preferred.

With respect to formula (IF) the term “benzothiophenyl” includes2-benzo[b]thiophenyl, 3-benzo[b]thiophenyl, 4-benzo[b]thiophenyl,5-benzo[b]thiophenyl, 6-benzo[b]thiophenyl and 7-benzo[b]thiophenyl.

With respect to formula (IF) the term “naphthyl” includes 1-naphthyl,and 2-naphthyl. 1-naphthyl is preferred.

With respect to formula (IF), similar terms specifying different numbersof C atoms take an analogous meaning. For example the terms “C₁-C₄alkyl” and “C₁-C₃ alkyl” mean a monovalent unsubstituted saturatedstraight-chain or branched-chain hydrocarbon radical having from 1 to 4and 1 to 3 carbon atoms respectively. The term “C₁-C₄ alkyl” includesmethyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, andtert-butyl. The term “C₁-C₃ alkyl” includes methyl, ethyl, n-propyl andiso-propyl.

With respect to formula (IF), it will be appreciated that when s is 2 or3, then each R⁵ and/or each R⁶ can be different. In the same way when tis 2 or 3, then each R⁷ and/or each R⁸ can be different.

Preferred compounds of formula (IF) are those of formula (IF′)

wherein R¹, R², R³, R⁴ and Ar₁ have the values defined in formula (IF)above.

Preferred compounds of formula (IF) are those of formula (IF″)

wherein R¹, R², R³, R⁴ and Ar₁ have the values defined in formula (IF)above.

Preferred compounds of formula (IF) are those wherein R¹ is C₁-C₆ alkyl,C₂-C₆ alkenyl, —(CH₂)_(m)—CF₃, —(CH₂)_(n)—S—(C₁-C₃ alkyl),—CH₂—COO—(C₁-C₂ alkyl), —(C₁-C₅ alkylene)-O—(C₁-C₃ alkyl), —(C₁-C₅alkylene)-O—(C₃-C₆ cycloalkyl), —(C₁-C₅ alkylene)-SO₂—(C₁-C₃ alkyl),—(C₁-C₅ alkylene)-OCF₃, —(C₁-C₆ alkylene)-OH, —(C₁-C₅ alkylene)-CN,—(CH₂)_(q)—Ar₂ or a group of formula (ia), (ib) or (ii)

R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, —X—, —Y—, p, q, r and s have the valuesdefined above; m is 1, 2 or 3; n is 1, 2 or 3; t is 2, 3 or 4; —Ar₁ isphenyl, pyridyl, thiazolyl or naphthyl; wherein said phenyl, pyridyl orthiazolyl group may be substituted with 1, 2 or 3 substituents eachindependently selected from halo, trifluoromethyl, cyano, C₁-C₄ alkyl,—O—(C₁-C₄ alkyl), —O—(C₁-C₄ difluoroalkyl), —O—(C₁-C₄ trifluoroalkyl),—S—(C₁-C₄ alkyl), —S—(C₁-C₂ trifluoroalkyl) and/or with 1 substituentselected from pyridyl, pyrazole, phenyl (optionally substituted with 1,2 or 3 halo substituents) and phenoxy (optionally substituted with 1, 2or 3 halo substituents); and wherein said naphthyl group may beoptionally substituted with 1, 2 or 3 substituents each independentlyselected from halo, trifluoromethyl, cyano, C₁-C₄ alkyl, —O—(C₁-C₄alkyl), —O—(C₁-C₄ difluoroalkyl), —O—(C₁-C₄ trifluoroalkyl), —S—(C₁-C₄alkyl), —S—(C₁-C₂ trifluoroalkyl); Ar₂ is naphthyl, pyridyl, thiazolyl,furyl, thiophenyl, benzothiophenyl, or phenyl, wherein said naphthyl,pyridyl, thiazolyl, furyl, thiophenyl, benzothiophenyl, or phenyl may besubstituted with 1, 2 or 3 substituents each independently selected fromhalo, C₁-C₄ alkyl, trifluoromethyl and —O—(C₁-C₄ alkyl).

Preferred compounds of formula (IF) are those wherein R² is hydrogen. Inanother preferred embodiment R³ and R⁴ are hydrogen. More preferably R²,R³ and R⁴ are hydrogen.

Preferred compounds of formula (IF) are those wherein each R⁵ and R⁶ ishydrogen. In another preferred embodiment each R⁷ and R⁸ is hydrogen.More preferably R⁵, R⁶, R⁷ and R⁸ are hydrogen.

Preferred compounds of formula (IF) are those wherein R¹ is C₁-C₆ alkyl.More preferably R¹ is n-propyl, 1-methylethyl (i-propyl), 2-methylpropyl(i-butyl), 2-methylbutyl, 2,2-dimethylbutyl.

Preferred compounds of formula (IF) are those wherein R¹ is —(C₄-C₅alkylene)-OH. More preferably R¹ is 2,2-dimethyl-2-hydroxyethyl or3,3-dimethyl-3-hydroxypropyl.

Preferred compounds of formula (IF) are those wherein R¹ is a group offormula (i) and each R⁵ and R⁶ is hydrogen. More preferably each R⁵, R⁶,R⁷ and R⁸ is hydrogen.

Preferred compounds of formula (IF) are those wherein R¹ is a group offormula (ii) and each R⁵ and R⁶ is hydrogen. More preferably each R⁵,R⁶, R⁷ and R⁸ is hydrogen.

Preferred compounds of formula (IF) are those wherein R¹ is a group offormula (i), r is 0 or 1, s is 2, t is 1 or 2, -Z is hydrogen and —X— is—O—, —S— or —SO₂—. More preferably R¹ is a group of formula (i), r is 0or 1, s is 2, t is 1 or 2, -Z is hydrogen and —X— is —O—, for exampletetrahydro-2H-pyran-4-yl, tetrahydrofuran-3-yl or(tetrahydrofuran-3-yl)methyl. Most preferably R¹ is a group of formula(i), r is 0, s is 2, t is 1 or 2, -Z is hydrogen and —X— is —O—, forexample tetrahydro-2H-pyran-4-yl or tetrahydrofuran-3-yl.

Preferred compounds of formula (IF) are those wherein R¹ is a group offormula (i), r is 0, s is 1, 2 or 3, t is 1, -Z is hydrogen and —X— is—CH₂—, for example cyclobutyl, cyclopentyl or cyclohexyl.

Preferred compounds of formula (IF) are those wherein R¹ is a group offormula (i), r is 1, s is 0, 1, 2 or 3, t is 1, -Z is hydrogen and —X—is —CH₂—.

Preferred compounds of formula (IF) are those wherein R¹ is a group ofthe formula (ia). More preferably R¹ is a group of the formula (ia) andeach R⁵, R⁶, R⁷and R⁸ is hydrogen.

Preferred compounds of formula (IF) are those wherein R¹ is a group ofthe formula (ib). More preferably R¹ is a group of the formula (ib), ris 1, t is 3, and each R⁷ and R⁸ is hydrogen.

Preferred compounds of formula (IF) are those wherein R¹ is—(CH₂)_(m)—CF₃. More preferably R¹ is —(CH₂)_(m)—CF₃ and m is 1, 2, or3.

Preferred compounds of formula (IF) are those wherein R¹ is—(CH₂)_(n)—S—(C₁-C₃ alkyl). More preferably R¹ is —(CH₂)₃—S—CH₃.

Preferred compounds of formula (IF) are those wherein R¹ is—CH₂—COO—(C₁-C₂ alkyl). More preferably R¹ is —CH₂—COOCH₃.

Preferred compounds of formula (IF) are those wherein R¹ is —(C₁-C₅alkylene)-O—(C₁-C₃ alkyl). More preferably R¹ is —(C₃-C₄ alkylene)-OCH₃.

Preferred compounds of formula (IF) are those wherein R¹ is —(C₁-C₅alkylene)-O—(C₃-C₆ cycloalkyl). More preferably R¹ is—CH₂-CH₂—O-cyclobutyl.

Preferred compounds of formula (IF) are those wherein R¹ is —(C₁-C₅alkylene)-SO₂—(C₁-C₃ alkyl).

Preferred compounds of formula (IF) are those wherein R¹ is —(C₁-C₅alkylene)-OCF₃. More preferably R¹ is —CH₂—CH₂—OCF₃.

Preferred compounds of formula (IF) are those wherein R¹ is —(C₁-C₅alkylene)-CN. More preferably R¹ is —(C₂-C₄ alkylene)-CN. Mostpreferably —CH₂—CH₂—CN or —CH₂—C(CH₃)₂—CN.

Preferred compounds of formula (IF) are those wherein R¹ is—(CH₂)_(q)—Ar₂, and q is 1. More preferably R¹ is —(CH₂)_(q)—Ar₂, q is 1and —Ar₂ is pyridyl, phenyl or phenyl substituted with 1, 2 or 3substituents each independently selected from halo, trifluoromethyl,C₁-C₄ alkyl or O—(C₁-C₄ alkyl).

Preferred compounds of formula (IF) are those wherein —Ar₁ is phenyl;phenyl substituted with 1, 2 or 3 substituents each independentlyselected from halo, trifluoromethyl and C₁-C₄ alkyl and/or with 1substituent selected from phenyl, phenyl substituted with 1, 2 or 3 halosubstituents, pyridyl, pyrazole, phenoxy and phenoxy substituted with 1,2 or 3 halo substituents; pyridyl; or pyridyl substituted with 1, 2 or 3substituents each independently selected from halo, trifluoromethyl andC₁-C₄ alkyl and/or with 1 substituent selected from phenyl and phenylsubstituted with 1, 2 or 3 halo substituents. More preferably —Ar₁ isphenyl or phenyl substituted with 1, 2 or 3 substituents eachindependently selected from halo, trifluoromethyl and C₁-C₄ alkyl and/orwith 1 substituent selected from phenyl, phenyl substituted with 1, 2 or3 halo substituents, pyridyl, pyrazole, phenoxy and phenoxy substitutedwith 1, 2 or 3 halo substituents. Most preferably —Ar₁ is phenylsubstituted with 1 or 2 substituents each independently selected fromhalo, trifluoromethyl and C₁-C₄ alkyl and/or with 1 substituent selectedfrom phenyl, phenyl substituted with 1, 2 or 3 halo substituents,pyridyl, pyrazole, phenoxy and phenoxy substituted with 1, 2 or 3 halosubstituents. Suitable —Ar₁ groups include, for example,2-methylthiophenyl, 2-methylphenyl, 2-fluorophenyl, 2-chlorophenyl,2-isopropoxyphenyl, 2-trifluoromethylphenyl, 2-difluoromethoxyphenyl,2-methoxyphenyl, 2-ethoxyphenyl, 2-(1,1′-biphenyl), 2-phenoxyphenyl,2-benzylphenyl, 3-trifluoromethoxyphenyl, 3-chlorophenyl,3-trifluoromethylphenyl, 3-methylphenyl, 3-trifluorothiomethoxyphenyl,3-methoxyphenyl, 5 4- trifluoromethylphenyl, 4-chlorophenyl,4-fluorophenyl, 3,5-dichlorophenyl, 3,5-dimethylphenyl,3-trifluoromethyl-5-fluorophenyl, 3,5-difluorophenyl,2,3-dichlorophenyl, 2,3-dimethylphenyl,2-chloro-3-trifluoromethylphenyl, 2-chloro-3-methylphenyl,2-methyl-3-chlorophenyl, 2,4-dichlorophenyl, 2,4-dimethyl,2,4-difluorophenyl, 2-chloro-4-fluorophenyl,2-trifluoromethyl-4-fluorophenyl, 2-fluoro-4-trifluoromethylphenyl,2-methyl-4-chlorophenyl, 2-methoxy-4-fluorophenyl,2-trifluoromethyl-5-fluorophenyl, 2,5-dimethylphenyl,4-fluoro-[1,1′-biphenyl]-2-yl, 2-chloro-5-fluorophenyl,2-(trifluoromethyl)-6-fluorophenyl, 2-chloro-6-fluorophenyl,3,4-dichlorophenyl, and 3-chloro-4-fluorophenyl. In general when —Ar₁ isphenyl substituted with pyridyl, 3-pyridyl is preferred.

Preferred compounds of formula (IF) are those wherein —Ar₁ is pyridyl orpyridyl substituted with 1, 2 or 3 substituents each independentlyselected from halo, trifluoromethyl and C₁-C₄ alkyl and/or with 1substituent selected from phenyl and phenyl substituted with 1, 2 or 3halo substituents. More preferably —Ar₁ is pyridyl substituted with 1 or2 substituents each independently selected from halo, trifluoromethyland C₁-C₄ alkyl and/or with 1 substituent selected from phenyl andphenyl substituted with 1, 2 or 3 halo substituents. Suitable —Ar₁groups include, for example, 3-phenyl-2-pyridyl. In general when —Ar₁ isa substituted pyridyl, substituted 2-pyridyl is preferred.

10. A compound of formula (IG)

wherein —X— is —S— or —O—; each R is independently selected from H orC₁-C₄ alkyl; R¹ is H, C₁-C₄ alkyl, C₁-C₄ alkoxy, halo, cyano,trifluoromethyl, trifluoromethoxy, —NR³R⁴, —CONR³R⁴, —COOR³ or a groupof the formula (i)

R²is C₁-C₄ alkyl, phenyl or phenyl substituted with 1, 2 or 3substituents each independently selected from C₁-C₄ alkyl, C₁-C₄ alkoxy,nitro, hydroxy, cyano, halo, trifluoromethyl, trifluoromethoxy, benzyl,benzyloxy, —NR⁶R⁷, —CONR⁶R⁷, COOR⁶, —SO₂NR⁶R⁷ and —SO₂R⁶; R⁵ is selectedfrom C₁-C₄ alkyl, C₁-C₄ alkoxy, carboxy, nitro, hydroxy, cyano, halo,trifluoromethyl, trifluoromethoxy, benzyl, benzyloxy, —NR⁸R⁹, —CONR⁸R⁹,—SO₂NR⁸R⁹ and —SO₂R⁸; R³, R⁴, R⁶, R⁷, R⁸ and R⁹ are each independentlyselected from H or C₁-C₄ alkyl; and -Z- is a bond, —CH₂—, or —O—; or apharmaceutically acceptable salt thereof.

With respect to formula (IG) the term “C₁-C₄ alkyl” means a monovalentunsubstituted saturated straight-chain or branched-chain hydrocarbonradical having from 1 to 4 carbon atoms. Thus the term “C₁-C₄ alkyl”includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl and tert-butyl.

With respect to formula (IG) the term “C₁-C₄ alkoxy” means a monovalentunsubstituted saturated straight-chain or branched-chain hydrocarbonradical having from 1 to 4 carbon atoms linked to the point ofsubstitution by an 0 atom. Thus the term “C₁-C₄ alkoxy” includesmethoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy.

With respect to formula (IG) the term “halo” or “halogen” means F, Cl,Br or I.

Preferred compounds of formula (IG) are those wherein —X— is —S—.

Preferred compounds of formula (IG) are those wherein —X— is —O—.

Preferred compounds of formula (IG) are those wherein R² is phenyl.

Preferred compounds of formula (IG) are those wherein all R groups arehydrogen.

Preferred compounds of formula (IG) are those represented by the formula(IIG)

wherein R¹ is H, C₁-C₄ alkyl, C₁-C₄ alkoxy, halo, cyano,trifluoromethyl, trifluoromethoxy, —NR³R⁴, —CONR³R⁴, —COOR³ or a groupof the formula (i)

R⁵ is selected from C₁-C₄ alkyl, C₁-C₄ alkoxy, carboxy, nitro, hydroxy,cyano, halo, trifluoromethyl, trifluoromethoxy, benzyl, benzyloxy,—NR⁸R⁹, —CONR⁸R⁹, —SO₂NR⁸R⁹ and —SO₂R⁸; R³, R⁴, R⁸ and R⁹ are eachindependently selected from H or C₁-C₄ alkyl; -Z- is a bond, —CH₂—, or—O—; or a pharmaceutically acceptable salt thereof.

Preferred compounds of formula (IG) or (IIG) are those wherein thesubstituent R¹ is in the three position of the pyridine ring as numberedin formula (IG) above. More preferably said substituent R¹ is H, C₁-C₄alkyl, halo, cyano, —CONR³R⁴, trifluoromethyl or a group of the formula(i). When R¹ is —CONR³R⁴, then R³ and R⁴ are both preferably H. When R¹is C₁-C₄ alkyl, then it is preferably methyl.

Preferred compounds of formula (IG) or (IIG) are those wherein thesubstituent R¹ is a group of the formula (i).

Preferred compounds of formula (IG) or (IIG) are those wherein R¹ is agroup of the formula (i), -Z- is a bond, and R⁵ is H or halo.

Preferred compounds of formula (IG) or (IIG) are those wherein R¹ is agroup of the formula (i), -Z- is —CH₂— or —O—, and R⁵ is H.

Preferred compounds of formula (IG) or (IIG) are those wherein thesubstituent R¹ is in the five position of the pyridine ring as numberedin formula (IG) above. More preferably said substituent R¹ is selectedfrom bromo, chloro or iodo.

Compounds within the scope of Formulae (IA), (IB), (IC), (ID), (IE),(IF) and (IG) above are inhibitors of norepinephrine reuptake. Certaincompounds within the scope of Formulae (IA), (IB), (IC), (ID), (IE),(IF) and (IG) above are selective inhibitors of norepinephrine reuptake.

Biogenic amine transporters control the amount of biogenic amineneurotransmitters in the synaptic cleft. Inhibition of the respectivetransporter leads to a rise in the concentration of thatneurotransmitter within the synaptic cleft. Compounds of Formulae (IA),(IB), (IC), (ID), (IE), (IF) and (IG) above and their pharmaceuticallyacceptable salts preferably exhibit a K_(i) value less than 500 nM atthe norepinephrine transporter as determined using the scintillationproximity assay as described below. More preferred compounds of Formulae(IA), (IB), (IC), (ID), (IE), (IF) and (IG) above and theirpharmaceutically acceptable salts exhibit a K_(i) value less than 100 nMat the norepinephrine transporter. More preferred compounds of Formulae(IA), (IB), (IC), (ID), (IE), (IF) and (IG) above and theirpharmaceutically acceptable salts exhibit a K_(i) value less than 50 nMat the norepinephrine transporter. Especially preferred compounds ofFormulae (IA), (IB), (IC), (ID), (IE), (IF) and (IG) above and theirpharmaceutically acceptable salts exhibit a K_(i) value less than 20 nMat the norepinephrine transporter. Preferably, these compoundsselectively inhibit the norepinephrine transporter relative to theserotonin and dopamine transporters by a factor of at least five, morepreferably by a factor of at least ten.

In addition, the compounds of Formulae (IA), (IB), (IC), (ID), (IE),(IF) and (IG) above of the present invention are preferably acid stable.Advantageously, they have a reduced interaction (both as substrate andinhibitor) with the liver enzyme Cytochrome P450 (CYP2D6). That is tosay, they preferably exhibit less than 75% metabolism via the CYP2D6pathway according to the CYP2D6 substrate assay described below and theypreferably exhibit an IC50 of >6 μM according to the CYP2D6 inhibitorassay described below.

While all compounds exhibiting norepinephrine reuptake inhibition areuseful for the methods of the present invention, certain are preferred.It is preferred that the norepinephrine reuptake inhibitor is selectivefor the reuptake of norepinephrine over the reuptake of otherneurotransmitters. It is also preferred that the norepinephrine reuptakeinhibitor does not exhibit signigicant direct agonist or antagonistactivity at other receptors. It is especially preferred that thenorepinephrine reuptake inhibitor be selected from atomoxetine,reboxetine, (S,S)-reboxetine,(R)-N-methyl-3-(2-methyl-thiophenoxy)-3-phenylpropylamine, and compoundsof Formulae (I), (IA), (IB), (IC), (ID), (IE), (IF) and (IG) above.

The present invention encompasses pharmaceutical compositions comprisingthe compounds disclosed herein, or pharmaceutically acceptable saltsthereof, together with a pharmaceutically acceptable carrier, diluent,or excipient.

It will be understood by the skilled reader that most or all of thecompounds used in the present invention are capable of forming salts,and that the salt forms of pharmaceuticals are commonly used, oftenbecause they are more readily crystallized and purified than are thefree bases. In all cases, the use of the pharmaceuticals described aboveas salts is contemplated in the description herein, and often ispreferred, and the pharmaceutically acceptable salts of all of thecompounds are included in the names of them.

Many of the compounds used in this invention are amines, and accordinglyreact with any of a number of inorganic and organic acids to formpharmaceutically acceptable acid addition salts. Since some of the freeamines of the compounds of this invention are typically oils at roomtemperature, it is preferable to convert the free amines to theirpharmaceutically acceptable acid addition salts for ease of handling andadministration, since the latter are routinely solid at roomtemperature. Acids commonly employed to form such salts are inorganicacids such as hydrochloric acid, hydrobromic acid, hydroiodic acid,sulfuric acid, phosphoric acid, and the like, and organic acids, such asp-toluenesulfonic acid, methanesulfonic acid, oxalic acid,p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid,benzoic acid, acetic acid and the like. Examples of suchpharmaceutically acceptable salts thus are the sulfate, pyrosulfate,bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate,dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide,iodide, acetate, propionate, decanoate, caprylate, acrylate, formate,isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate,succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate,hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate,dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate,xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate,citrate, lactate, b-hydroxybutyrate, glycollate, tartrate,methanesulfonate, prop anesul fonate, naphthalene-1-sulfonate,naphthalene-2-sulfonate, mandel ate and the like. Preferredpharmaceutically acceptable salts are those formed with hydrochloricacid.

Pharmaceutically acceptable salts of the compounds of Formulae (IA),(IB), (IC), (ID) (IE), (IF) and (IG) above include acid addition salts,including salts formed with inorganic acids, for example hydrochloric,hydrobromic, nitric, sulphuric or phosphoric acids, or with organicacids, such as organic carboxylic or organic sulphonic acids, forexample, acetoxybenzoic, citric, glycolic, o- mandelic-l, mandelic-dl,mandelic d, maleic, mesotartaric monohydrate, hydroxymaleic, fumaric,lactobionic, malic, methanesulphonic, napsylic, naphtalenedisulfonic,naphtoic, oxalic, palmitic, phenylacetic, propionic, pyridyl hydroxypyruvic, salicylic, stearic, succinic, sulphanilic, tartaric,2-hydroxyethane sulphonic, toluene-p-sulphonic, and xinafoic acids.

In addition to the pharmaceutically acceptable salts, other salts canserve as intermediates in the purification of compounds, or in thepreparation of other, for example pharmaceutically acceptable, acidaddition salts, or are useful for identification, characterization, orpurification.

The present invention encompasses the administration of a compositionthat exhibits (preferably selective) norepinephrine reuptake inhibitoractivity. The composition can comprise one or more agents that,individually or together, inhibit norepinephrine reuptake preferably ina selective manner.

Dosages

The dosages of the drugs used in the methods of the present inventionmust, in the final analysis, be set by the physician in charge of thecase using knowledge of the drugs, the properties of the drugs alone orin combination as determined in clinical trials, and the characteristicsof the patient including diseases other than that for which thephysician is treating the patient. General outlines of the dosages, andsome preferred dosages, are as follows: intravenous, or intradermaladministration), intra-pulmonary, vaginal, rectal, intranasal,ophthalmic, or intraperitoneal administration, or by an implantableextended release device. Oral administration is preferred. The route ofadministration can be varied in any way, limited by the physicalproperties of the drugs, the convenience of the patient and thecaregiver, and other relevant circumstances (Remington's PharmaceuticalSciences (1990) 18th Edition, Mack Publishing Co.).

The pharmaceutical compositions are prepared in a manner well known inthe pharmaceutical art. The carrier or excipient can be a solid,semi-solid, or liquid material that can serve as a vehicle or medium forthe active ingredient. Suitable carriers or excipients are well known inthe art. The pharmaceutical composition can be adapted for oral,inhalation, parenteral, or topical use and can be administered to thepatient in the form of tablets, capsules, aerosols, inhalants,suppositories, solutions, suspensions, or the like.

The compounds of the present invention can be administered orally, forexample, with an inert diluent or capsules or compressed into tablets.For the purpose of oral therapeutic administration, the compounds can beincorporated with excipients and used in the form of tablets, troches,capsules, elixirs, suspensions, syrups, wafers, chewing gums and thelike. These preparations should contain at least 4% of the compound ofthe present invention, the active ingredient, but can be varieddepending upon the particular form and can conveniently be between 4% toabout 70% of the weight of the unit. The amount of the compound presentin compositions is such that a suitable dosage will be obtained.Preferred compositions and preparations according to the presentinvention can be determined by a person skilled in the art.

The tablets, pills, capsules, troches, and the like can also contain oneor more of the following adjuvants: binders such as microcrystallinecellulose, gum tragacanth or gelatin; excipients such as starch orlactose, disintegrating agents such as alginic acid, Primogel, cornstarch and the like; lubricants such as magnesium stearate or Sterotex;glidants such as colloidal silicon dioxide; and sweetening agents suchas sucrose or saccharin can be added or a flavoring agent such aspeppermint, methyl salicylate or orange flavoring. When the dosage unitform is a capsule, it can contain, in addition to materials of the abovetype, a liquid carrier such as polyethylene glycol or a fatty oil.

Atomoxetine:

In adults and older adolescents: from about 5 mg/day to about 200mg/day; preferably in the range from about 60 to about 150 mg/day; morepreferably from about 60 to about 130 mg/day; and still more preferablyfrom about 50 to about 120 mg/day;

In children and younger adolescents: from about 0.2 to about 3.0mg/kg/day; preferably in the range from about 0.5 to about 1.8mg/kg/day;

Reboxetine: Racemic reboxetine can be administered to an individual inan amount in the range of from about 2 to about 20 mg per patient perday, more preferably from about 4 to about 10 mg/day, and even morepreferably from about 6 to about 10 mg/day. Depending on theformulation, the total daily dosage can be administered in smalleramounts up to two times per day. A preferred adult daily dose ofoptically pure (S,S) reboxetine can be in the range of from about 0.1 mgto about 10 mg, more preferably from about 0.5 mg to about 8 to 10 mg,per patient per day. The effective daily dose of reboxetine for a childis smaller, typically in the range of from about 0.1 mg to about 4 toabout 5 mg/day. Treatments using compositions containing optically pure(S,S)-reboxetine are about 5 to about 8.5 times more effective ininhibiting the reuptake of norepinephrine than compositions containing aracemic mixture of (R,R)- and (S,S)-reboxetine, and therefore lowerdoses can be employed. PCT International Publication No. WO 01/01973contains additional details concerning the dosing of (S,S) reboxetine.

Compounds of formula I: from about 0.01 mg/kg to about 20 mg/kg;preferred daily doses are from about 0.05 mg/kg to 10 mg/kg; morepreferably from about 0.1 mg/kg to about 5 mg/kg;

Compounds of formulae (IA), (lB), (IC), (ID), (IE), (IF) and (IG) above:from about 5 to about 500 mg, more preferably from about 25 to about 300mg, of the active ingredient per patient per day.

Administration

The compounds disclosed herein can be administered by various routes,for example systemically via oral (including buccal or sublingual),topical (including buccal, sublingual, or transdermal), parenteral(including subcutaneous, intramuscular, Other dosage unit forms cancontain other various materials that modify the physical form of thedosage unit, for example, as coatings. Thus, tablets or pills can becoated with sugar, shellac, or other coating agents. A syrup cancontain, in addition to the present compounds, sucrose as a sweeteningagent and certain preservatives, dyes and colorings and flavors.Materials used in preparing these various compositions should bepharmaceutically pure and non-toxic in the amounts used.

A formulation useful for the administration of R-(−)-N-methyl3-((2-methylphenyl)oxy)-3-phenyl-1-aminopropane hydrochloride(atomoxetine) comprises a dry mixture of R-(−)-N-methyl3-((2-methylphenyl)oxy)-3-phenyl-1-aminopropane hydrochloride with adiluent and lubricant. A starch, such as pregelatinized corn starch, isa suitable diluent and a silicone oil, such as dimethicone, a suitablelubricant for use in hard gelatin capsules. Suitable formulations areprepared containing about 0.4 to 26% R-(−)-N-methyl3-((2-methylphen-yl)oxy)-3-phenyl-1-aminopropane hydrochloride, about 73to 99% starch, and about 0.2 to 1.0% silicone oil. Tables 1 and 2illustrate particularly preferred formulations: TABLE 1 Ingredient (%)2.5 mg 5 mg 10 mg 18 mg 20 mg 25 mg 40 mg 60 mg R-(−)-N-methyl 3- 1.242.48 4.97 8.94 9.93 12.42 19.87 22.12 ((2-methylphenyl) oxy)-3-phenyl-1- aminopropane hydrochloride Dimethicone 0.5 0.5 0.5 0.5 0.5 0.50.5 0.5 Pregelatinized 98.26 97.02 94.53 90.56 89.57 87.08 79.63 77.38Starch

TABLE 2 Ingredient (mg/capsule) 2.5 mg 5 mg 10 mg 18 mg 20 mg 25 mg 40mg 60 mg R-(−)-N-methyl 3- 2.86 5.71 11.43 20.57 22.85 28.57 45.71 68.56((2-methylphenyl) oxy)-3- phenyl-1- aminopropane hydrochlorideDimethicone 1.15 1.15 1.15 1.15 1.15 1.15 1.15 1.55 Pregelatinized225.99 223.14 217.42 208.28 206.00 200.28 183.14 239.89 Starch CapsuleFill Weight 230 230 230 230 230 230 230 310 (mg) Capsule Size 3 3 3 3 33 3 2

For the purpose of parenteral therapeutic administration, the compoundsof the present invention can be incorporated into a solution orsuspension. These preparations typically contain at least 0.1% of acompound of the invention, but can be varied to be between 0.1 and about90% of the weight thereof. The amount of the compound of formula Ipresent in such compositions is such that a suitable dosage will beobtained. The solutions or suspensions can also include one or more ofthe following adjuvants: sterile diluents such as water for injection,saline solution, fixed oils, polyethylene glycols, glycerine, propyleneglycol or other synthetic solvents; antibacterial agents such as benzylalcohol or methyl paraben; antioxidants such as ascorbic acid or sodiumbisulfite; chelating agents such as ethylene diaminetetraacetic acid;buffers such as acetates, citrates or phosphates and agents for theadjustment of tonicity such as sodium chloride or dextrose. Theparenteral preparation can be enclosed in ampoules, disposable syringesor multiple dose vials made of glass or plastic. Preferred compositionsand preparations are able to be determined by one skilled in the art.

The compounds of the present invention can also be administeredtopically, and when done so the carrier can suitably comprise asolution, ointment, or gel base. The base, for example, can comprise oneor more of the following: petrolatum, lanolin, polyethylene glycols,bees wax, mineral oil, diluents such as water and alcohol, andemulsifiers, and stabilizers. Topical formulations can contain aconcentration of the compound, or its pharmaceutical salt, from about0.1 to about 10% w/v (weight per unit volume).

The compositions are preferably formulated in a dosage unit form, i.e.,physically discrete units suitable as unitary doses for human subjectsand other mammals, each unit containing a predetermined quantity ofactive material calculated to produce the desired therapeutic effect, inassociation with a suitable pharmaceutical carrier, diluent, orexcipient.

The following examples are provided to illustrate various aspects of thepresent invention, and should not be construed to be limiting thereof inany way.

Preparation of Compounds of Formula (1A)

Compounds of formula (IA) may be prepared by conventional organicchemistry techniques and also by solid phase synthesis. In the presentspecification the abbreviation “boc” refers to the N-protecting groupt-butyloxycarbonyl. In the present specification the abbreviation “TFA”refers to trifluoroacetic acid. In the present specification theabbreviation “DMF” refers to dimethylformamide. In the presentspecification the abbreviation “SPE” refers to solid phase extraction.In the present specification the abbreviation “ACE-Cl” refers toct-chloroethyl chloroformate.

When R8 is H, a suitable three-step conventional synthesis is outlinedin Scheme 1A shown below.

A boc-protected 4-piperidone (IIA) is reductively aminated with an amineto provide a 4-amino-piperidine (IIIAa or IIIAb). A second reductiveamination with an aldehyde or ketone provides a boc-protected compoundof formula (IA) (IVA). The boc group is removed under acidic conditionsto provide a compound of formula (IA) (where R8 is H). If desired, thecompound of formula (IA) (where R8 is H) may be converted to a suitablesalt by addition of a suitable quantity of a suitable acid. In theschemes above (and below) R1 to R7, R9, R10 and n are as previouslydefined, m is 0, 1 or 2 and R11 and R12 are chosen such thatR11-CH—R12=R1.

Although the boc N-protecting group is used in the above illustration,it will be appreciated that other N-protecting groups (for exampleacetyl, benzyl or benzoxycarbonyl) could also be used together with adeprotection step appropriate for the N-protecting group used.Similarly, other reducing agents (for example NaBH₄ or LiAIH₄) may beused in the reductive amination steps and other acids (for example HCl)may be used in the deprotection step.

As an alternative to the second reductive amination step, compound IIIAaor IIIAb may be subjected to an alkylation step as shown in Scheme 1Bbelow (L represents a suitable leaving group—for example Br or tosyl).

Once again, N-protection other than boc may also be used together with asuitable deprotection step. Similarly, bases other than potassiumcarbonate (e.g NaH) may be used for the alkylation step

Using essentially the same chemical reactions as in the first schemeabove, the compounds of formula (IA) (where R8 is H) may also beprepared by a solid phase parallel synthesis technique as outlined inScheme 1C shown below.

A piperidone hydrate is attached to a polystyrene resin to provide aresin bound piperidone (VA). Aliquots are reductively aminated toprovide a resin bound secondary amine (VIA) that can undergo a furtherreductive amination with an aldehyde or ketone to give the tertiaryamine (VIIA). Acidic cleavage from the resin and SPE provides compoundsof formula (IA) (where R8 is H) which may be purified by ion exchangemethods using, for example, the SCX-2 ion exchange resin.

Although NaBH(OAc)₃ is used in the above illustration, it will beappreciated that other reducing agents (for example NaBH₄ or LiAIH₄) maybe used in the reductive amination steps and other acids (for exampleHCl) may be used in the deprotection step. Solid phase resins other thanthe p-nitrophenylcarbonate-polystyrene resin illustrated above may alsobe employed.

When R8 is C₁-C₄alkyl, a conventional synthetic route is outlined inScheme 1D shown below.

A benzyl-protected 4-piperidone (VIIIA) is alkylated with analkyllithium reagent to provide a 4-amino-piperidinot (IXA). Treatmentwith an alkylnitrile or alkylamide under strongly acidic conditionsprovides a secondary amide (XA) which may be deprotected, boc-protectedand reduced to provide a secondary amine (XIA). Alkylation of thesecondary amine (XIA) followed by removal of the boc group provides acompound of formnula (IA) (where R8 is C₁-C₄alkyl). In the scheme aboveL is a leaving group as previously defined and R13 is chosen such thatR13—CH₂═R1.

Although the benzyl and boc N-protecting groups are used in the aboveillustration, it will be appreciated that other N-protecting groupscould also be used in their place together with deprotection stepsappropriate for those N-protecting groups. Similarly, other reducingagents may be used in the amidecarbonyl reduction step and otherorganometallics or bases may be used in the respective alkylation steps.

Preparation of Compounds of Formula (IB)

A general scheme outlining the synthetic routes to compounds of Formulae(IB) wherein Y is OH is shown below (Scheme 1B). For clarity, Ar₂ isshown as phenyl and Ry and Rz are shown as H. It will be appreciatedthat analogous methods could be applied for other possible identities ofAr₂, Ry and Rz.

Compounds of Formulae (IB) can be prepared by conventional organicchemistry techniques from an N-benzyl-ketomorpholine of type 1 B byaddition of a suitable organometallic derivative (method A), or via theaddition of a suitable organometallic reagent to an epoxide of type 2B(method B), as outlined in Scheme 1B.

The racemic intermediates of type 1B can be obtained as outlined inScheme 2B by condensation of an N-benzyl cyanomorpholine 5B (J. Med.Chem. 1993, 36, pp 683-689) with a suitable aryl organometallic reagentfollowed by acid hydrolysis. Chiral HPLC separations of the racemicN-benzyl-aryl-ketomorpholine of type 1B gives the required singleenantiomer, i.e., the (2S)-N-benzyl-aryl-ketomorpholine of type 6B(Scheme 2B).

Condensation of a chiral (2S)-N-benzyl-aryl-ketomorpholine of type 6Bwith a commercially available benzylic magnesium halide or a benzylicmagnesium halide prepared using standard Grignard techniques from thecorresponding halo-benzylic derivative gives a tertiary alcohol of type3B without any observed epimerisation of the existing asymmetric center(ee's/de's determinations can be carried out using chiral HPLC) and withvery high overall diastereoisomeric excesses (see Scheme 3B). The finalcompounds of type 4B can be obtained after cleavage of the N-benzylprotecting group on a compound of type 3B. The deprotection can be doneusing catalytic palladium hydrogenolysis, or carbamate exchange withACE-Cl (1-Chloroethyl chloroformate), giving intermediates of type 7B,followed by methanolysis as shown in Scheme 3B.

The intermediates 3B can be further elaborated using for exampleorganometallic type couplings between an ortho bromide derivative oftype 8B and an arylboronic acid as shown in Scheme 4B. For clarity, Ar₁and its substituent (R₁) are shown as phenyl and substitution occurs atthe 2-position. It will be appreciated that analogous methods could beapplied for other possible identities of Ar₁ and R₁ and other possiblesubstitution positions. This approach can also be carried out by solidphase synthetic methods as described in more detail in the specificexamples below.

An alternative route for the preparation of the compounds of Formulae(IB) is method B (see Scheme 1B). Formation of the intermediate epoxidesof type 2B from racemic N-benzyl-ketomorpholines of type 1B, can be doneusing for example trimethyl sulfoxonium iodide and a suitable base, forexample sodium hydride. Condensation of 2B with a commercially availablearyl organometallic, or an aryl organometallic prepared from thecorresponding halo aryl derivative, gives the intermediates of type 3B,as mixtures of diastereoisomers. Final deprotections can be done asdescribed above (see Scheme 3B). Final compounds made using method B canbe purified using chiral HPLC.

Compounds of Formula (IB) of the present invention wherein Y is OR and Ris C₁-C₄ alkyl, can be synthesized by standard alkylation ofintermediates of type 3B prior to deprotection of the morpholine N-atomas shown in Scheme 5B. Suitable strong bases will be known to the personskilled in the art and include, for example, sodium hydride. Similarly,suitable alkylating agents will be known to the person skilled in theart and include, for example, C₁-C₄ alkyl halides such as methyl iodide.

Preparation of Compounds of Formula (IC)

Compounds of formula (IC) may be prepared by conventional organicchemistry techniques from N-benzyl-cyanomorpholine 1C (Route A) orN-benzyl-morpholinone 2C (Route B) as outlined in Scheme IC below: Forclarity, X is shown as phenyl and R′ and R¹ are shown as H. It will beappreciated that analogous methods could be applied for other possibleidentities of X, R′ and R¹.

More detail of Route A is given in Scheme 2C:

The amino alcohol 4Ca can be obtained by reaction ofN-benzyl-cyanomorpholine 1C with a Grignard reagent, followed by acidhydrolysis to give racemic phenyl ketone 3C which may be separated onchiral HPLC. (2S)-Phenyl ketone 3Ca may then be reduced with DIP-Cl togive 4Ca in high diastereomeric excess. The amino alcohol 4Ca isconverted into benzyl bromide 5Ca, to give the desired N-substitutedaryl thio morpholines after displacement with the requisite aryl thiol.N-substituted aryloxy morpholines may be obtained in an analogous mannerby displacement with the requisite hydroxyaryl compound. Alternatively,N-substituted aryloxy morpholines may be obtained by addition of astrong base, such as sodium hydride, to the amino alcohol 4Ca to form anucleophilic alkoxide followed by an SNAr reaction with an Ar groupsubstituted with a suitable leaving group (e.g. F). Deprotection of thetertiary amine gives the final products.

Detail of route B is given in Scheme 3C:

Treatment of N-benzyl morpholinone 2C with a strong base such as lithiumdiisopropylamide at low temperature followed by addition of benzaldehydegives aldol adducts 6Ca-6Cd as a 2:1 mixture of diastereomer pairs6Ca,6Cb and 6Cc,6Cd, which may be separated using conventionalchromatographic techniques. Reduction with a borane reagent at elevatedtemperatures gives diasteremeric amino alcohol pairs 4Ca,4Cb and 4Cc,4Cdrespectively.

Amino alcohol pair 4Ca,4Cb may be converted to bromide 5Ca,5Cb andfurther to racemic aryl thio morpholines as outlined in Scheme 4C. Aminoalcohol pair 4Cc,4Cd may be converted into the corresponding mesylate.Displacement with the requisite thiol, followed by removal of thenitrogen protecting group furnishes aryl thiol morpholines as racemicmixtures of two diastereomers. The racemic aryl thiol morpholines may beseparated into enantiomerically pure products using chiral HPLCtechnology. N-substituted aryloxy morpholines may be obtained in ananalogous manner by displacement with the requisite hydroxyarylcompound.

Aryl-substituted morpholines 33C, 35C, 37C may be obtained frommorpholinone 2C as outlined in Scheme 5C:

An alternative route to 9C is outlined in Scheme 6C. This route makesuse of a chiral auxiliary and gives 9C in enantiomerically pure form.

Pretaration of Compounds of Formula (ID)

Compounds of formula (ID) may be prepared using the following methods.General schemes outlining the synthetic routes used to prepare racemicproducts are given below. All active racemates may be separated intosingle enantiomers using chiral HPLC and may be readily converted intosuitable salts.

Compounds of formula (ID) wherein Ar is (i) and R^(2c) is H may beprepared as shown in Scheme 1D below:

Quinolin-2-one 1D or its corresponding 4-oxo and 4-thio derivatives canbe N-arylated using modified conditions to those reported by Buchwald,(J. Am. Chem. Soc., 123, 2001, p. 7727). For example the quinolin-2-one1D is reacted with 3 equivalents of Ar—Br wherein Ar is (i) and R^(2c)is H, 0.2 equivalents of trans-cyclohexanediamine, 0.2 equivalent ofcopper iodide (CuI), 2.1 equivalents of potassium carbonate (K₂CO₃), inan organic solvent such as 1,4-dioxane at a temperature of 125° C.overnight. The resulting N-arylated quinolin-2-one 2D can be alkylatedby treatment with a strong base such as lithium hexamethyldisilazide(LiHMDS) at temperatures of −78° C. in a suitable organic solvent suchas tetrahydrofuran (THF), followed by the addition of an alkyl halidesuch as alkyl iodide to give the corresponding 3-alkylated-N-arylatedquinolin-2-one derivative 3D. Using the same alkylating conditions abovewith a 1,2-dihaloethane, such as 1-bromo-2-chloroethane, or a1,3-dihalopropane, such as 1-bromo-3-chloropropane, as alkylating agentsprovides 4D or 5D wherein n is 2 or 3 respectively. These halo analogueswere chosen as ideal precursors to the desired amine products. Forinstance, treatment of 4D or 5D with aqueous methylamine, in thepresence of a catalytic amount of a suitable iodide, such as potassiumiodide (KI), in ethanol at 100° C. provided the racemic amine products6D and 7D respectively, in moderate yields.

Compounds of formula (ID) wherein Ar is (i), R^(2c) is H and n is 3 maybe prepared using alternative chemistry as shown in Scheme 2D.

Quinolin-2-ones 2D and 3D can be alkylated using the aforementionedalkylating procedure using an allyl halide e.g. allyl bromide as thealkylating agent to give the corresponding3-allyl-N-arylated-quinolin-2-ones 11D. Said allyl analogues could thenbe converted to the corresponding primary alcohols 12D by ahydroboration procedure involving a suitable borane, such as 9-BBN in asuitable solvent such as THF. Oxidative work up using for examplereaction conditions such as aqueous hydrogen peroxide in a solvent suchas ethanol, in the presence of a suitable base, such as sodiumhydroxide, gave moderate to good yields of alcohol products after columnchromatography purification. The alcohols were cleanly converted intotheir mesylates, by reaction of a mesyl halide such as mesyl chloride inthe presence of a suitable base such as triethylamine in a suitablesolvent such as THF at a suitable temperature such as 0° C. to roomtemperature. The resulting mesylates are used directly in the aminationstep described above in Scheme 1D to provide good yields of the finalracemic targets 13D.

In order to prepare a range of N-arylated analogues advancedintermediates were prepared that could undergo N-arylations with a rangeof substituted aryl halides, such as aryl bromides or iodides, 2 and3-halothiophenes, 2 and 3-halofurans or 2 and 3-halopyrroles. Thesynthetic route used to prepare intermediates 19D is shown below inScheme 3D.

Compounds of formula (ID) wherein n is 3 may be prepared as shown inScheme 3D. This method is particularly suitable for compounds wherein Aris (i) and R^(2c) is H or Ar is (ii), wherein —Y— is —S—.

Quinolin-2-one 1D can be protected using a suitable amide-protectinggroup such as those described in T. W. Greene, “Protective Groups inOrganic Synthesis”, John Wiley and Sons, New York, N.Y., 1991, hereafterreferred to as “Greene”. For example quinolin-2-one 1D can be protectedwith a 4-methoxybenzyl group. The protection reaction can be carried outfor example using a suitable base, such as sodium hydride in a suitablesolvent, such as dimethylfornamide, followed by reaction with a4-methoxybenzyl halide, such as 4-methoxybenzyl chloride, to give thecorresponding N-protected derivative 14D in good yield. Thisintermediate can be converted directly to the allyl analogue 16Da,wherein R¹═H, in a manner described earlier or converted into the alkylanalogue 15D which can be subsequently alkylated with a allyl halide togive the allyl analogue 16Db, wherein R¹ is C₁-C₄ alkyl. Using the samehydroboration, mesylation and amination sequence described in Scheme 2Dprovided both amines 18Da-b. Deprotection of protected quinolin-2-onecould be achieved using any suitable deprotection conditions as thoseshown in Greene. For example, the 4-methoxybenzyl group could be cleavedcleanly using trifluoroacetic acid and anisole at 65° C. The resultantproduct could be selectively protected on the secondary amine with asuitable nitrogen protecting group as those described in Greene. Forexample, the secondary amine can be protected with a Boc group. Thereaction can be carried out with Boc anhydride in a suitable solventsuch as THF to provide multi gram quantities of 19Da-b. Reaction of19Da-b with various aryl bromides using the previously described N-arylation conditions, deprotection using suitable deprotectingconditions such as those described in Greene gave a range of finalracemic targets 21Da-b or 22Da-b. For example, for compounds protectedwith a Boc group they can be deprotected in the presence oftrifluoroacetic acid (TFA) in a suitable organic solvent such asdichoromethane (DCM).

Intermediates 19Da-b wherein R³ is a halo group, for example chloro orbromo, can be used to provide compounds of formula (ID) wherein R³ is aphenyl group, such as compound 24D, via a Suzuki coupling, see Scheme 4Dbelow.

Intermediates 19Da-b, wherein R³ is for example bromo can be N-protectedwith a suitable amide protecting group for example 4-methoxybenzyl asdescribed in Scheme 3D above and then coupled with phenylboronic acidunder Suzuki conditions to provide the phenyl analogues 23D.Deprotection of the 4-methoxybenzyl group with TFA, followed byprotection of the resulting secondary amine with a suitable nitrogenprotecting group such as Boc followed by subsequent N-arylation and Bocdeprotection using the previously described methodology gave the finaltarget 24D.

It will be appreciated that compounds of formula (IDa) wherein R³ isbromo or chloro can be prepared as shown in Schemes 1D to 4D abovestarting from the corresponding haloquinolin-2-ones. Alternatively, theycan be prepared from the corresponding quinolin-2-one 1D wherein R³ ishydrogen as mentioned above including an extra step comprising thehalogenation of a suitable intermediate at some stage of the synthesis.For example quinolin-2-one 1D in Scheme 2D can be halogenated usingN-chlorosuccinimide in a suitable solvent such as DMF at a suitabletemperature such as room temperature to give the corresponding6-chloro-quinolin-2-one ID wherein R³ is Cl.

Alternatively intermediates (19Da-b) wherein R³ is H in Scheme 3D can behalogenated in the presence of N-chloro and N-bromosuccinimide in asuitable solvent such as DMF to give the corresponding 6-chloro and6-bromoquinolin-2-ones (20Da-c).

It will be appreciated that Schemes ID to 4D above relate to methods forthe preparation of compounds of formula (ID) wherein Ar is (i) andR^(2c) is hydrogen. Compounds of formula (ID) wherein Ar is (i) andR^(2c) can be other than hydrogen, can be prepared using any of thegeneral methods mentioned above, starting from the correspondingN-arylated quinolin-2-one 27D. A general method for preparing saidintermediates is illustrated in Scheme 5D. Commercially available3-(2-Bromo-phenyl)-propionic acids 25D can be converted to amide 26Dusing standard amide coupling conditions and converted to the N-arylatedquinolin-2-ones 27D by an intramolecular, palladium catalysedcyclisation according to the method of Buchwald et al (Tetrahedron,1996, 52, p.7525).

Preparation of Compounds of Formula (IE)

Compounds of formula (IE) may be prepared by conventional organicchemistry techniques and also by solid phase synthesis. Compounds offormula (IE) can be prepared via the 3-aminopyrrolidine intermediate offormula (IVE) as illustrated in the Scheme 1E below:

Commercially available 3-hydroxypyrrolidine of formula (IIIE) wherein R²is hydrogen, can be protected using a suitable nitrogen-protecting groupsuch as those described in T. W. Greene, “Protective Groups in OrganicSynthesis”, John Wiley and Sons, New York, N.Y., 1991, hereafterreferred to as “Greene”. For example 3-R-hydroxypyrrolidine (IIIE) canbe protected with a tert-butoxycarbonyl group, (boc). The protectionreaction can be carried out for example using Boc anhydride in asuitable solvent such as for example tetrahydrofuran (THF) ordichloromethane (DCM) in the presence of a base such as tryethylamine(TEA) or 4—(dimethylamino)pyridine (DMAP). It will be appreciated thatfor compounds of formula (IE) wherein R² is C₁-C₂ alkyl, the3-hydroxypyrrolidine of formula (IIIE) can be prepared from the readilyavailable 3-pyrrolidinone via addition of the appropriate C₁-C₂ alkylorganometallic. The hydroxy group of theN-protected-3-hydroxypyrrolidine can be converted into a suitableleaving group (L) such as for example chloride, bromide, iodide ormesylate. For example the N-protected-hydroxypyrrolidine can beconverted to the mesylate in the presence of mesyl chloride and asuitable base such as triethylamine in a solvent such as DCM. Saidmesylate is subsequently displaced with the corresponding azide in asuitable solvent such as dimethylformnamide (DMF) or dimethylsulphoxide(DMSO). This azide intermediate can be converted to the correspondingN-protected-aminopyrrolidine of formula (IVE) via hydrogenation in thepresence of a suitable catalyst such as Palladium on charcoal and in asuitable solvent such as methanol or ethanol.

For compounds of formula (IE) wherein R⁴ is H, intermediate (IVE) can bealkylated via reductive alkylation with a ketone of formula R³—CO—Ar₁wherein R³ and Ar, have the values for formula (IE) above. The reductivealkylation can be carried out for example as a hydrogenation reaction inthe presence of a suitable catalyst such as Palladium on charcoal and asuitable solvent such as for example ethanol. Alternatively, saidreductive alkylation can be carried out in the presence of a suitableborane such as sodium triacetoxyborohydride, NaBH(OAc)₃ and optionallyin the presence of a suitable acid such as acetic acid, in a suitablesolvent such as for example dichoroethane (DCE).

Alternatively, intermediate of formula (VE) wherein R⁴ is H can beprepared as shown in Scheme 2E below by reductive alkylation of readilyavailable 3-aminopyrrolidine of formula (VIE) wherein R² has the valuesdefined for formula (IE) above, followed by the protection of thenitrogen in the pyrrolidine ring using a suitable protecting group suchas those defined in Greene.

For example the reductive alkylation can be carried out in the presenceof a ketone of formula Ar₁—CO—R³ wherein Ar₁ and R³ have the valuesdefined for formula (IE) above. Initial condensation of the aminopyrrolidine with the ketone is undertaken in the presence of a suitableacid such as p-toluenesulphonic acid, in a suitable solvent such astoluene. The resultant imino pyrrolidine intermediate can then beprotected with for example a boc group. The reaction can be carried outin the presence of boc anhydride and a suitable base such as DMAP, in asuitable solvent such as DCM. Said imine is reduced via hydrogenation inthe presence of a suitable catalyst such as palladium on charcoal, in asuitable solvent such as ethanol to give the corresponding amine offormula (VE).

Intermediate of formula (VE) can be converted to compounds of formula(VIIIE) via reductive alkylation with an aldehyde of formula R⁹—CHO,wherein R⁹ is chosen such that R⁹—CH₂═R¹ and R¹ has the values definedfor formula (IE) above. The reductive alkylation can be carried outusing standard methods, for instance as those mentioned above with theketone Ar₁—CO—R³.

For example a compound of formula (VE) can be alkylated with R⁹—CHO inthe presence of a suitable borane, such as NaBH(OAc)₃, optionally in thepresence of an acid such as acetic acid, in the presence of a suitablesolvent such as dichloroethane (DCE).

For compounds of formula (IE) wherein R³ and R⁴ are hydrogen thealkylation of intermediate (VE) can be carried out with a compound offormula Ar₁CH₂L₁ wherein L₁ is a suitable leaving group such as chloro,bromo, iodo or mesylate, in the presence of a suitable base such aspotassium carbonate and a suitable solvent such as acetonitrile, to givethe corresponding intermediate of formula (VIIIE)_(a). It will beappreciated that the same reaction can be carried out using Ar₁—CR³R⁴-L₁wherein R³ and R⁴ are C₁-C₂ alkyl.

Compounds of formula (IE) wherein R¹ is —CH₂—COO—(C₁-C₂ alkyl) can beprepared by reacting intermediate (VE) with a compound of formulaL₂-CH₂—COO—(C₁-C₂ alkyl) wherein L₂ is a suitable leaving group such asfor example bromo, chloro or iodo. Said reaction can be carried out inthe presence of a suitable base such as sodium hydride, in a suitablesolvent such as dimethylformamide.

Compounds of formula (IE) wherein R¹ is —(CH₂)_(m)—CF₃ can be preparedby reacting intermediate (VE) with a compound of formula HOOC—(CH₂)_(m)₁ —CF₃, wherein m₁ is 0, 1 or 2. The acid may be activated as itsanhydride or acyl chloride, and is reacted in the presence of a suitablebase such as triethylamine and a catalytic amount of DMAP, in a suitablesolvent such as DCM. The resulting amide can be reduced to the amine offormula (VIIIE), in the presence of a suitable borane. For example, forcompounds wherein m is 1, the reduction can be carried out in thepresence of BH₃-Me₂S borane-dimethyl sulphide complex, in a suitablesolvent such as THF.

Compounds of formula (IE) wherein R¹ is —C₁-C₆ alkylene)-OH can beprepared by reacting intermediate (VE) with an epoxide. For example forcompounds wherein R¹ is —CH₂—C(CH₃)₂—OH, the intermediate of formula(VE) is reacted with 2,2-dimethyloxirane, in a suitable solvent such asaqueous ethanol.

Alternatively compounds of formula (IE) wherein R¹ is—(C₁-C₆alkylene)-OH can be prepared by reacting intermediate (VE) withan w-haloalkanoate, such as methylbromoacetate, in the presence of abase such a sodium hydrogen carbonate in a solvent such as acetonitrile.The intermediate ester is then reacted with 2 equivalents of methylmagnesium bromide in THF to yield the tertiary alcohol(VIIIE)_(d):

It will be appreciated that the Scheme 8E above applies to alkylenechains longer than —CH₂—.

Compounds of formula (IE) wherein R¹ is —C₂-C₆ alkenyl,—(CH₂)_(n)—S—(C₁-C₃ alkyl), —(C₁-C₅ alkylene)-O—(C₁-C₃ alkyl), —(C₁-C₅alkylene)-O—(C₃-C₆ cycloalkyl), —(C₁-C₅ alkylene)-SO₂—(C₁-C₃ alkyl), —(C—C₅ alkylene)-OCF₃, or —(C₁-C₅ alkylene)-CN, can be prepared viaalkylation of intermediate (VE) with a compound of formula L₂-C₂-C₆alkenyl, L₂-(CH₂)_(n)—S—(C₁-C₃ alkyl), L₂-(C₁-C₅ alkylene)-O—(C₁-C₃alkyl), L₂-(C₁-C₅ alkylene)-O—(C₃-C₆ cycloalkyl), L₂-(C₁-C₅alkylene)-SO₂—(C₁-C₃ alkyl), L₂-(C₁-C₅ alkylene)-OCF₃, or L₂-(C₁-C₅alkylene)-CN respectively, wherein L₂ is a suitable leaving group suchas chloro, bromo, iodo or mesylate, in the presence of a suitable basesuch as potassium carbonate and a suitable solvent such as acetonitrile,to give the corresponding intermediate of formula (VIIIE)_(e).

Compounds of formula (IE) wherein R is a group of formula (i) can beprepared using the synthesis illustrated in Scheme 10E for compoundswherein R¹ is 4-tetrahydropyranyl. The compound of formula (IVE) can bealkylated via reductive alkylation using standard methods, as thosementioned above with the ketone Ar₁—CO—R³. For example compound offormula (IVE) can be alkylated with 4-tetrahydropyranone in the presenceof a suitable borane, such as sodium borohydride or NaBH(OAc)₃,optionally in the presence of an acid such as acetic acid, in thepresence of a suitable solvent such as dichloroethane (DCE). Then, thesecondary amine can be alkylated with a compound of formula Ar₁CH₂L₁wherein L₁ is a suitable leaving group such as chloro, bromo, iodo ormesylate, in the presence of a suitable base such as potassium carbonateand a suitable solvent such as acetonitrile, to give the correspondingintermediate of formula (VIIIE)_(f). It will be appreciated that asmentioned above the same reaction can be carried out using Ar₁—CR³R⁴-L,wherein R³ and R⁴are C₁-C₂ alkyl.

It will be appreciated that for compounds of formula (IE) wherein R¹ isa group of formula (i) and r is 1 then the reductive amination can becarried out using the same reaction conditions but using thecorresponding homologous aldehyde of formula

instead of the corresponding 4-tetrahydropyranone. Alternatively,compounds of formula (IE) wherein R¹ is a group of formula (i) and r is1 can be prepared via formation of an amide, followed by reduction ofthis amide bond to the corresponding amine as shown in Scheme 11E below:

The coupling reaction can be carried out using standard methods known inthe art. The reduction of the amide bond can also be carried by generalmethods known in the art for example using the same reduction conditionsas those used in Scheme 6, such as in the presence of BH₃-Me₂S(borane-dimethyl sulphide complex), in a suitable solvent such as THF.

Alternatively, compounds of formula (IE) wherein R¹ is a group offormula (i) wherein r is 0 can be prepared by a process illustrated inScheme 12E for compounds wherein -Z is hydrogen, s is 1, t is 2, eachR⁵, R⁶, R⁷ and R⁸ are hydrogen and —X— is —O—, (i.e. R¹ is2-tetrahydrofuranyl). The compound of formula (IVE) can be alkylatedwith a compound of formula:

wherein L₄ is a suitable leaving group such as chloro, bromo, iodo,mesylate or tosylate, in the presence of a suitable base such aspotassium carbonate and a suitable solvent such as acetonitrile, to givethe corresponding secondary amine which can be subsequently alkylatedwith a compound of formula Ar₁CH₂L₁ wherein L₁ is a suitable leavinggroup such as chloro, bromo, iodo or mesylate, in the presence of asuitable base such as potassium carbonate and a suitable solvent such asacetonitrile, to give the corresponding intermediate of formula(VIIIE)_(f). It will be appreciated that as mentioned above the samereaction can be carried out using Ar₁—CR³R⁴-L₁ wherein R³ and R⁴areC₁-C₂ alkyl.

The tetrahydrofuranyl intermediates can be prepared from thecorresponding 3-hydroxytetrahydrofuran, wherein the hydroxy group isconverted into the leaving group using standard methods.

Compounds of formula (IE) wherein R¹ is a group of formula (i) and —X—is —SO₂— can be prepared from the corresponding intermediates(VIIIE)_(f), wherein the thioether is oxidized to the correspondingsulphoxide as shown in Scheme 13E below:

Compounds of formula (IE) wherein R¹ is a group of formula (ii) can beprepared using the synthesis illustrated in Scheme 14E for compoundswherein R¹ is oxabicyclo[3,2,1]octan-3-yl. The compound of formula (IVE)can be alkylated via reductive alkylation using standard methods, asthose mentioned above with the ketone Ar₁—CO—R³. For example compound offormula (IVE) can be alkylated with oxabicyclo[3,2,1]octan-3-one in thepresence of a suitable borane, such as sodium borohydride or NaBH(OAc)₃,optionally in the presence of an acid such as acetic acid, in thepresence of a suitable solvent such as dichloroethane (DCE). Then, thesecondary amine can be alkylated with a compound of formula Ar₁CH₂L₁wherein L₁ is a suitable leaving group such as chloro, bromo, iodo ormesylate, in the presence of a suitable base such as potassium carbonateand a suitable solvent such as acetonitrile, to give the correspondingintermediate of formula (VIIIE)₁. It will be appreciated that asmentioned above the same reaction can be carried out using Ar₁—CR³R⁴-L₁wherein R³ and R⁴are C₁-C₂ alkyl.

The oxabicyclo[3,2,1]octan-3-one intermediate is prepared according tothe method described in A E Hill, G Greenwood and H M R Hoffmann JACS1973, 95, 1338. It will be appreciated that for compounds of formula(IE) wherein R is a group of formula (i) and r is 1 then the reductiveamination can be carried out using the same reaction conditions butusing the corresponding homologous aldehyde of formula

instead of the corresponding oxabicyclo[3,2,1]octan-3-one.

Compounds of formula (IE) wherein Ar₁ is a substituted or unsubstitutedpyridyl group can be prepared by a process illustrated in Scheme 15E forcompounds wherein R³ and R⁴ are hydrogen and Ar₁ is 3-phenylpyrid-2-yl.

The compound of formula (IVE) can be alkylated via reductive alkylationusing standard methods, as those mentioned above with the ketoneAr₁—CO—R³. For example compound of formula (IVE) can be alkylated withan aldehyde of formula:

in the presence of a suitable borane, such as sodium borohydride orNaBH(OAc)₃, optionally in the presence of an acid such as acetic acid,in the presence of a suitable solvent such as dichloroethane (DCE).Then, the secondary amine can be alkylated using the geheral methodsdescribed above for the incorporation of R¹. The intermediate aldehydecan be prepared via reduction of readily available methyl 3-phenylpicolinate to the corresponding alcohol and subsequent oxidation to thealdehyde as shown in Scheme 16E below.

The reduction step can be carried out in the presence of a suitablereducing agent such as lithium borohydride in a suitable solvent such astetrahydrofuran. The oxidation to the aldehyde can be carried out underSwern conditions such as oxalyl chloride and DMSO in DCM.

Compounds of formula (IE) wherein Ar₁ is a substituted or unsubstitutedphenyl group can be prepared by a process illustrated in Scheme 17E forcompounds wherein R³ and R⁴ are hydrogen and Ar₁ is 2-(3-pyridyl)phenyl.

The compound of formula (IVE) can be alkylated via reductive alkylationusing standard methods, as those mentioned above with the ketoneAr₁—CO—R³. For example compound of formula (IVE) can be alkylated withan aldehyde of formula:

in the presence of a suitable borane, such as sodium borohydride orNaBH(OAc)₃, optionally in the presence of an acid such as acetic acid,in the presence of a suitable solvent such as dichloroethane (DCE).Then, the secondary amine can be alkylated using the general methodsdescribed above for the incorporation of R¹. The intermediate aldehydecan be prepared from the commercially available 2-formyl phenyl boronicacid via palladium coupling in the presence of 3-bromopyridine, asuitable palladium catalyst such as Pd(PPh₃)₄ and a suitable base suchas potassium carbonate in a suitable solvent such as acetonitrile, asshown in Scheme 18E below.

Compounds of formula (IE) wherein Ar₁ is a phenyl group substituted witha 1-pyrazole group can be prepared by a process illustrated in Scheme19E.

The pyrazole group can be incorporated by reacting a compound of formula(VIIIE)_(m′), wherein L₅ is a suitable leaving group such as bromo,chloro or iodo, with pyrazole in the presence of a suitable base such aspotassium carbonate and a catalytic amount of copper iodide in asuitable solvent such as for example DMF. The compound of formula(VIIIE)_(m′) can be prepared by any of the methods mentioned above forcompounds wherein Ar1 is a phenyl group substituted with a halogen atomsuch as chloro, bromo or iodo.

It will be appreciated that any of the intermediates (VIIIE),(VIIIE)_(a-m) are then deprotected using suitable deprotectingconditions such as those discussed in Greene, to give the correspondingcompounds of formula (IE). For example if the protecting group is a bocgroup, the deprotection reaction can be carried out in trifluoroaceticacid in a suitable solvent such as DCM. Alternatively the reaction canbe carried out in ethanolic hydrochloric acid.

Compounds of formula (IE) wherein R³ and R⁴ are both hydrogen may alsobe prepared by solid phase synthesis by the route shown below in Scheme21E below.

The sequence is preferably performed on a polystyrene resin. The processmay be run in a combinatorial fashion such that all possible compoundsfrom sets of precursors Ar₁CHO and R⁹CHO may be prepared, wherein R⁹ ischosen such that R⁹—CH₂═R¹, and R¹ and Ar₁ have the values defined abovefor formula (IE). The sequence is performed without characterisation ofthe resin-bound intermediates. In step (i)3-trifluoroacetamido-pyrrolidine is bound to a solid support by reactionwith 4-nitrophenyl carbonate activated polystyrene resin in the presenceof a base, such as N,N-diisopropylethylamine, in a solvent such as DMF.In step (ii), the trifluoroacetamido protecting group is cleaved byhydrolysis with a base such as aqueous lithium hydroxide. In step (iii)the primary amine is then condensed with a substituted benzaldehyde inthe presence of a dehydrating agent, such as trimethylorthoformate, toform the intermediate imine. In step (iv) the imine is reduced with aborane reducing agent, such as sodium cyanoborohydride, in a solventsuch as DMF, containing acetic acid. In step (v) the resultant secondaryamine is then reductively alkylated with an aldehyde in the presence ofa reducing agent such as sodium triacetoxyborohydride in a solvent, suchas DMF. In step (vi) the desired product is finally cleaved from theresin with acid, such as aqueous trifluoroacetic acid.

Preparation of Compounds of Formula (IF)

Compounds of formula (IF) may be prepared by conventional organicchemistry techniques and also by solid phase synthesis.

Compounds of formula (IF′) can be prepared by the general methodsillustrated below. It will be appreciated that the same methods can beused for compounds of formula (IF″) with the only difference that thenitrogen atom of the quinuclidines does not need to be protected as itis already a tertiary amine as it is explained in more detail below withreference to Scheme 1F.

Compounds of formula (IF′) can be prepared via the 3-aminopiperidineintermediate of formula (IVF) as illustrated in Scheme 1F below:

Commercially available 3-hydroxypiperidine of formula (IIIF) wherein R²is hydrogen, can be protected using a suitable nitrogen-protecting groupsuch as those described in T. W. Greene, “Protective Groups in OrganicSynthesis”, John Wiley and Sons, New York, N.Y., 1991, hereafterreferred to as “Greene”. For example 3-R-hydroxypiperidine (IIIF) can beprotected with a tert-butoxycarbonyl group, (boc). The protectionreaction can be carried out for example using Boc anhydride in asuitable solvent such as for example tetrahydrofuran (THF) ordichloromethane (DCM) in the presence of a base such as triethylamine(TEA) or 4-(dimethylamino)pyridine (DMAP). It will be appreciated thatfor compounds of formula (IF) wherein R² is C₁-C₂ alkyl, the3-hydroxypiperidine of formula (IIIF) can be prepared from the readilyavailable 3-pyrrolidinone via addition of the appropriate C₁-C₂ alkylorganometallic. The hydroxy group of the N-protected-3-hydroxypiperidinecan be converted into a suitable leaving group (L) such as for examplechloride, bromide, iodide or mesylate. For example theN-protected-hydroxypiperidine can be converted to the mesylate in thepresence of mesyl chloride and a suitable base such as triethylamine ina solvent such as DCM. Said mesylate is subsequently displaced with thecorresponding azide in a suitable solvent such as dimethylformamide(DMF) or dimethylsulphoxide (DMSO). This azide intermediate can beconverted to the corresponding N-protected-aminopiperidine of formula(IV) via hydrogenation in the presence of a suitable catalyst such asPalladium on charcoal and in a suitable solvent such as methanol orethanol.

For compounds of formula (IF) wherein R⁴ is H, intermediate (IVF) can bealkylated via reductive alkylation with a ketone of formula R³—CO—Ar₁wherein R³ and Ar₁ have the values for formula (IF) above. The reductivealkylation can be carried out for example as a hydrogenation reaction inthe presence of a suitable catalyst such as Palladium on charcoal and asuitable solvent such as for example ethanol. Alternatively, saidreductive alkylation can be carried out in the presence of a suitableborane such as sodium triacetoxyborohydride, NaBH(OAc)₃ and optionallyin the presence of a suitable acid such as acetic acid, in a suitablesolvent such as for example dichoroethane (DCE).

Alternatively, intermediate of formula (VF) wherein R⁴ is H can beprepared as shown in Scheme 2F below by reductive alkylation of readilyavailable 3-aminopiperidine of formula (VIF) wherein R² has the valuesdefined for formula (IF) above, followed by the protection of thenitrogen in the piperidine ring using a suitable protecting group suchas those defined in Greene.

For example the reductive alkylation can be carried out in the presenceof a ketone of formula Ar₁—CO—R³ wherein Ar₁ and R³ have the valuesdefined for formula (IF) above. Initial condensation of the aminopiperidine with the ketone is undertaken in the presence of a suitableacid such as p-toluenesulphonic acid, in a suitable solvent such astoluene. The resultant imino piperidine intermediate can then beprotected with for example a boc group. The reaction can be carried outin the presence of boc anhydride and a suitable base such as DMAP, in asuitable solvent such as DCM. Said imine is reduced via hydrogenation inthe presence of a suitable catalyst such as palladium on charcoal, in asuitable solvent such as ethanol to give the corresponding amine offormula (VF).

Intermediate of formula (VF) can be converted to compounds of formula(VIIIF) via reductive alkylation with an aldehyde of formula R⁹—CHO,wherein R⁹ is chosen such that R⁹—CH₂═R¹ and R¹ has the values definedfor formula (IF) above. The reductive alkylation can be carried outusing standard methods, for instance as those mentioned above with theketone Ar₁—CO—R³.

For example a compound of formula (VF) can be alkylated with R⁹—CHO inthe presence of a suitable borane, such as NaBH(OAc)₃, optionally in thepresence of an acid such as acetic acid, in the presence of a suitablesolvent such as dichloroethane (DCE).

For compounds of formula (IF) wherein R³ and R⁴ are hydrogen thealkylation of intermediate (VF) can be carried out with a compound offormula Ar₁CH₂L₁ wherein L₁ is a suitable leaving group such as chloro,bromo, iodo or mesylate, in the presence of a suitable base such aspotassium carbonate and a suitable solvent such as acetonitrile, to givethe corresponding intermediate of formula (VIIIF)_(a). It will beappreciated that the same reaction can be carried out using Ar₁—CR³R⁴—L₁wherein R³ and R⁴are C₁-C₂ alkyl.

Compounds of formula (IF) wherein R¹ is —CH₂—COO—(C₁-C₂ alkyl) can beprepared by reacting intermediate (VF) with a compound of formulaL₂-CH₂—COO—(C₁-C₂ alkyl) wherein L₂ is a suitable leaving group such asfor example bromo, chloro or iodo. Said reaction can be carried out inthe presence of a suitable base such as sodium hydride, in a suitablesolvent such as dimethylformamide.

Compounds of formula (IF) wherein R¹ is —(CH₂)_(m)—CF₃ can be preparedby reacting intermediate (VF) with a compound of formulaHOOC—(CH₂)_((m-1))—CF₃. The acid may be activated as its anhydride oracyl chloride, and is reacted in the presence of a suitable base such astriethylamine and a catalytic amount of DMAP, in a suitable solvent suchas DCM. The resulting amide can be reduced to the amine of formula(VIIF)_(c) in the presence of a suitable borane. For example, forcompounds wherein m is 1, the reduction can be carried out in thepresence of BH₃—Me₂S borane-dimethyl sulphide complex, in a suitablesolvent such as THF.

Compounds of formula (IF) wherein R¹ is —(C₁-C₆ alkylene)-OH can beprepared by reacting intermediate (VF) with an epoxide. For example forcompounds wherein R¹ is —CH₂—C(CH₃)₂—OH, the intermediate of formula(VF) is reacted with 2,2-dimethyloxirane, in a suitable solvent such asaqueous ethanol.

Alternatively compounds of formula (IF) wherein R¹ is—(C₁-C₆alkylene)-OH can be prepared by reacting intermediate (VF) withan ω-haloalkanoate, such as methylbromoacetate, in the presence of abase such a sodium hydrogen carbonate in a solvent such as acetonitrile.The intermediate ester is then reacted with 2 equivalents of methylmagnesium bromide in THF to yield the tertiary alcohol(VIIIF)_(d):

It will be appreciated that the Scheme 8F above applies to alkylenechains longer than —CH₂—.

Compounds of formula (IF) wherein R¹ is —C₂-C₆ alkenyl,—(CH₂)_(n)—S—(C₁-C₃ alkyl), —(C₁-C₅ alkylene)-O—(C₁-C₃ alkyl), —(C₁-C₅alkylene)-O—(C₃-C₆ cycloalkyl), —(C₁-C₅ alkylene)-SO₂—(C₁-C₃ alkyl),—(C₁-C₅ alkylene)-OCF₃, or —(C₁-C₅ alkylene)-CN, can be prepared viaalkylation of intermediate (VF) with a compound of formula L₂-C₂-C₆alkenyl, L₂-(CH₂)_(n)—S—(C₁-C₃ alkyl), L₂-(C₁-C₅ alkylene)-O—(C₁ -C₃alkyl), L₂-(C₁-C₅ alkylene)-O—(C₃-C₆ cycloalkyl), L₂-(C₁-C₅alkylene)-SO₂—(C₁-C₃ alkyl), L₂-(C₁-C₅ alkylene)-OCF₃, or L₂-(C₁-C₅alkylene)-CN respectively, wherein L₂ is a suitable leaving group suchas chloro, bromo, iodo or mesylate, in the presence of a suitable basesuch as potassium carbonate and a suitable solvent such as acetonitrile,to give the corresponding intermediate of formula (VIIIF)e.

Compounds of formula (IF) wherein R¹ is a group of formula (i) can beprepared using the synthesis illustrated in Scheme 10F for compoundswherein R¹ is 4-tetrahydropyranyl. The compound of formula (IVF) can bealkylated via reductive alkylation using standard methods, as thosementioned above with the ketone Ar₁—CO—R³. For example a compound offormula (IVF) can be alkylated with 4-tetrahydropyranone in the presenceof a suitable borane, such as sodium borohydride or NaBH(OAc)₃,optionally in the presence of an acid such as acetic acid, in thepresence of a suitable solvent such as dichloroethane (DCE). Then, thesecondary amine can be alkylated with a compound of formula Ar₁CH₂L₁wherein L₁ is a suitable leaving group such as chloro, bromo, iodo ormesylate, in the presence of a suitable base such as potassium carbonateand a suitable solvent such as acetonitrile, to give the correspondingintermediate of formula (VIIIF)_(f). It will be appreciated that asmentioned above the same reaction can be carried out using Ar₁—CR³R⁴-L,wherein R³ and R⁴are C₁-C₂ alkyl.

It will be appreciated that for compounds of formula (IF) wherein R¹ isa group of formula (i) and r is 1 then the reductive amination can becarried out using the same reaction conditions but using thecorresponding homologous aldehyde of formula

instead of the corresponding 4-tetrahydropyranone. Alternatively,compounds of formula (IF) wherein R¹ is a group of formula (i) and r is1 can be prepared via formation of an amide, followed by reduction ofthis amide bond to the corresponding amine as shown in Scheme 11F below:

The coupling reaction can be carried out using standard methods known inthe art. The reduction of the amide bond can also be carried out bygeneral methods known in the art for example using the same reductionconditions as those used in Scheme 6F, such as in the presence ofBH₃—Me₂S (borane-dimethyl sulphide complex), in a suitable solvent suchas THF.

Alternatively, compounds of formula (IF) wherein R¹ is a group offormula (i) wherein r is 0 can be prepared by a process illustrated inScheme 12F for compounds wherein -Z is hydrogen, s is 1, t is 2, eachR⁵, R⁶, R⁷ and R⁸ are hydrogen and —X— is —O—, (i.e. R¹ istetrahydrofuran-3-yl). The compound of formula (IVF) can be alkylatedwith a compound of formula:

wherein L₄ is a suitable leaving group such as chloro, bromo, iodo,mesylate or tosylate, in the presence of a suitable base such aspotassium carbonate and a suitable solvent such as acetonitrile, to givethe corresponding secondary amine which can be subsequently alkylatedwith a compound of formula Ar₁CH₂L₁ wherein L₁ is a suitable leavinggroup such as chloro, bromo, iodo or mesylate, in the presence of asuitable base such as potassium carbonate and a suitable solvent such asacetonitrile, to give the corresponding intermediate of formula(VIIIF)_(f). It will be appreciated that as mentioned above the samereaction can be carried out using Ar₁—CR³R⁴-L, wherein R³ and R⁴areC₁-C₂ alkyl.

The tetrahydrofuranyl intermediates can be prepared from thecorresponding 3-hydroxytetrahydrofuran, wherein the hydroxy group isconverted into the leaving group using standard methods.

Compounds of formula (IF) wherein R is a group of formula (i) and —X— is—SO₂— can be prepared from the corresponding intermediates (VIIIF)_(f),wherein the thioether is oxidized to the corresponding sulphoxide asshown in Scheme 13F below:

Compounds of formula (IF) wherein R¹ is a group of formula (ii) can beprepared using the synthesis illustrated in Scheme 14F for compoundswherein R¹ is oxabicyclo[3,2,1]octan-3-yl. The compound of formula (IVF)can be alkylated via reductive alkylation using standard methods, asthose mentioned above with the ketone Ar¹—CO—R³. For example compound offormula (IVF) can be alkylated with oxabicyclo[3,2,1]octan-3-one in thepresence of a suitable borane, such as sodium borohydride or NaBH(OAc)₃,optionally in the presence of an acid such as acetic acid, in thepresence of a suitable solvent such as dichloroethane (DCE). Then, thesecondary amine can be alkylated with a compound of formula Ar₁CH₂L₁wherein L₁ is a suitable leaving group such as chloro, bromo, iodo ormesylate, in the presence of a suitable base such as potassium carbonateand a suitable solvent such as acetonitrile, to give the correspondingintermediate of formula (VIIIF)_(j). It will be appreciated that asmentioned above the same reaction can be carried out using Ar₁—CR³R⁴-L,wherein R³ and R⁴are C₁-C₂ alkyl.

The oxabicyclo[3,2,1]octan-3-one intermediate is prepared according tothe method described in A E Hill, G Greenwood and H M R Hoffmann JACS1973, 95, 1338. It will be appreciated that for compounds of formula(IF) wherein R¹ is a group of formula (i) and r is 1 then the reductiveamination can be carried out using the same reaction conditions butusing the corresponding homologous aldehyde of formula

instead of the corresponding oxabicyclo[3,2,1]octan-3-one.

Compounds of formula (IF) wherein Ar₁ is a substituted or unsubstitutedpyridyl group can be prepared by a process illustrated in Scheme 15F forcompounds wherein R³ and R⁴ are hydrogen and Ar₁ is 3-phenylpyrid-2-yl.

The compound of formula (IVF) can be alkylated via reductive alkylationusing standard methods, as those mentioned above with the ketoneAr₁—CO—R³. For example compound of formula (IVF) can be alkylated withan aldehyde of formula:

in the presence of a suitable borane, such as sodium borohydride orNaBH(OAc)₃, optionally in the presence of an acid such as acetic acid,in the presence of a suitable solvent such as dichloroethane (DCE).Then, the secondary amine can be alkylated using the general methodsdescribed above for the incorporation of R¹. The intermediate aldehydecan be prepared via reduction of readily available methyl 3-phenylpicolinate to the corresponding alcohol and subsequent oxidation to thealdehyde as shown in Scheme 16F below.

The reduction step can be carried out in the presence of a suitablereducing agent such as lithium borohydride in a suitable solvent such astetrahydrofuran. The oxidation to the aldehyde can be carried out underSwem conditions such as oxalyl chloride and DMSO in DCM.

Compounds of formula (IF) wherein Ar₁ is a substituted or unsubstitutedphenyl group can be prepared by a process illustrated in Scheme 17F forcompounds wherein R³ and R⁴ are hydrogen and Ar₁ is 2-(3-pyridyl)phenyl.

The compound of formula (IVF) can be alkylated via reductive alkylationusing standard methods, as those mentioned above with the ketoneAr₁—CO—R³. For example compound of formula (IVF) can be alkylated withan aldehyde of formula:

in the presence of a suitable borane, such as sodium borohydride orNaBH(OAc)₃, optionally in the presence of an acid such as acetic acid,in the presence of a suitable solvent such as dichloroethane (DCE).Then, the secondary amine can be alkylated using the general methodsdescribed above for the incorporation of R¹. The intermediate aldehydecan be prepared from the commercially available 2-formyl phenyl boronicacid via palladium coupling in the presence of 3-bromopyridine, asuitable palladium catalyst such as Pd(PPh₃)₄ and a suitable base suchas potassium carbonate in a suitable solvent such as acetonitrile, asshown in Scheme 18F below.

Compounds of formula (IF) wherein Ar₁ is a phenyl group substituted witha 1-pyrazole group can be prepared by a process illustrated in Scheme19F.

The pyrazole group can be incorporated by reacting a compound of formula(VIIIF)_(m), wherein L₅ is a suitable leaving group such as bromo,chloro or iodo, with pyrazole in the presence of a suitable base such aspotassium carbonate and a catalytic amount of copper iodide in asuitable solvent such as for example DMF. The compound of formula(VIIIF)_(m), can be prepared by any of the methods mentioned above forcompounds wherein Ar1 is a phenyl group substituted with a halogen atomsuch as chloro, bromo or iodo.

It will be appreciated that any of the intermediates (VIIIF),(VIIIF)_(a-m) are then deprotected using suitable deprotectingconditions such as those discussed in Greene, to give the correspondingcompounds of formula (IF). For example if the protecting group is a bocgroup, the deprotection reaction can be carried out in trifluoroaceticacid in a suitable solvent such as DCM. Alternatively the reaction canbe carried out in ethanolic hydrochloric acid.

Compounds of formula (IF) wherein R³ and R⁴ are both hydrogen may alsobe prepared by solid phase synthesis by the route shown below as Scheme21F.

The sequence is preferably performed on a polystyrene resin. The processmay be run in a combinatorial fashion such that all possible compoundsfrom sets of precursors Ar₁CHO and R⁹CHO may be prepared, wherein R⁹ ischosen such that R⁹—CH₂═R¹, and R¹ and Ar₁ have the values defined abovefor formula (IF). The sequence is performed without characterisation ofthe resin-bound intermediates. In step (i)3-trifluoroacetamido-piperidine is bound to a solid support by reactionwith 4-nitrophenyl carbonate activated polystyrene resin in the presenceof a base, such as N,N-diisopropylethylamine, in a solvent such as DMF.In step (ii), the trifluoroacetamido protecting group is cleaved byhydrolysis with a base such as aqueous lithium hydroxide. In step (iii)the primary amine is then condensed with a substituted benzaldehyde inthe presence of a dehydrating agent, such as trimethylorthoformate, toform the intermediate imine. In step (iv) the imine is reduced with aborane reducing agent, such as sodium cyanoborohydride, in a solventsuch as DMF, containing acetic acid. In step (v) the resultant secondaryamine is then reductively alkylated with an aldehyde in the presence ofa reducing agent such as sodium triacetoxyborohydride in a solvent, suchas DMF. In step (vi) the desired product is finally cleaved from theresin with acid, such as aqueous trifluoroacetic acid.

Preparation of Compounds of Formula (IG)

Compounds of formula (IG) may be prepared by conventional organicchemistry techniques from N-protected-2-cyanomorpholines as outlined inError! Reference source not found.G below, wherein R and R² have thevalues defined for formula (IG) above and P is a suitable nitrogenprotecting group such as those described in T. W. Greene, “ProtectiveGroups in Organic Synthesis”, John Wiley and Sons, New York, N.Y., 1991,hereafter referred to as “Greene”. For example a suitable nitrogenprotecting group is a benzyl group:

The phenyl ketone (IIIG) can be obtained by reaction ofN-protected-2-cyanomorpholine with a Grignard reagent, followed by acidhydrolysis to give the racemic phenyl ketone which may be separated onchiral HPLC.

Compounds of formula (IG) can be prepared from the N-protectedmorpholine ketone intermediate of formula (IIIG), as illustrated inError! Reference source not found.G below:

The ketone is stereoselectively reduced to the corresponding (2S) or(2R) alcohol of formula (IVG) or (IVG)_(a) using standard methods knownin the art. For example it can be reduced in the presence of[(−)-B-chlorodiisopinocampheylborane] in a suitable solvent such astetrahydrofuran (THF) to provide the (2S) alcohol.

The resulting alcohol is then transformed into a suitable leaving groupL. Suitable leaving groups include halo groups, such as bromo, chloro oriodo and sulfonate groups, such as mesylate. When L is a halo group, thealcohol used will be the (2S) enantiomer (IVG) and it will be reactedwith inversion of stereochemistry. For example, when L is bromo, thebromination reaction can be carried out in the presence of a brominatingagent such as triphenylphosphine dibromide, in a suitable solvent suchas chloroform. When L is a mesylate group, the alcohol used will be the(2R) enantiomer (IVG)_(a) and it will be reacted with retention ofstereochemistry in the presence of mesylate chloride and a suitablebase.

The resulting intermediate of formula (VG) can then be converted intothe corresponding methylethanethioate of formula (VIG) via displacementof the leaving group with a suitable thiolacetate salt such as potassiumthiolacetate in the presence of a suitable solvent such as a mixture ofdimethylformamide (DMF) and tetrahydrofuran (THF).

The methanethiol intermediate of formula (VIIG) can be prepared viareaction of the methylethanethioate (VIG) with a suitable thiomethoxidesuch as sodium thiomethoxide in the presence of a suitable solvent suchas methanol (one can use a variety of bases but thiomethoxide ispreferred because it also acts as a reducing agent and preventsoxidation of thiol hence inhibiting dimerisation; Ref: O. B. Wallace &D. M. Springer, Tetrahedron Letters, 1998, 39 (18), pp2693-2694).

The pyridyl portion of the molecule is incorporated via general methodsknown in the art. A particularly useful method is the reaction of themethanethiol (VIIG) with a compound of the formula

wherein R¹ has the values defined above and L₁ is a suitable leavinggroup such as fluoro, bromo, chloro, iodo or mesylate, in the presenceof suitable base such as sodium hydride, cesium fluoride or sodiummethoxide, in a suitable solvent such as DMF.

Compounds of formula (IG) wherein —X— is —O— can be prepared in ananalogous fashion by reaction of the (2S) alcohol of formula (IVG) witha compound of formula (VIIIG) above.

The final step for the preparation of compounds of formula (IG)comprises deprotection of the morpholine ring. Conditions for thedeprotection depend on the protecting group chosen. Suitabledeprotecting conditions can be found in Greene. For example when thenitrogen protecting group is a benzyl group, the deprotection reactioncan be carried out in the presence of polymer supported diisopropylamine(PS-DIEA) and 1-chloroethyl chloroformate (ACE-Cl) in a suitable solventsuch as dichloromethane, followed by reaction with methanol to givecompounds of formula (IG).

Compounds of formula (IG) can alternatively be prepared by thederivatisation of a suitable substituent in the pyridyl ring to give thedesired substituent R¹ as shown in Scheme 3G below. For examplecompounds of formula (IG) wherein —R¹ is —CF₃ can be prepared viareaction of the intermediate (IXG)′ wherein L₂ is introduced into themolecule in place of R¹ in formula (VIIIG) as shown in Error! Referencesource not found.G above. The group L₂ is a suitable leaving group suchas for example iodo, bromo, chloro or fluoro. The leaving group isconverted into a trifluoromethyl group via reaction in the presence ofcopper iodide, a suitable base such as for example potassium fluoride,and a suitable source of a trifluoromethyl group such as for example(trifluoromethyl)trimethylsilane, in a suitable solvent such as forexample a mixture of DMF and N-methyl-pyrrolidinone (NMP). The resultingcompound of formula (XG) is deprotected using the methodology describedabove.

Compounds of formula (IG) wherein —X— is —S— can alternatively beprepared 20 directly from the intermediate methylethanethioate offormula (VIG) as illustrated in Error! Reference source not found.Gbelow.

The reaction can be carried out via general methods known in the art.For example, the intermediate (VIG) can be reacted with a compound offormula (VIIIG), wherein R¹ and L₁ have the values defined above, in thepresence of a suitable base such as sodium methoxide, in a suitablesolvent such as for example DMF.

The resulting compound of formula (IXG) wherein —X— is —S— is thendeprotected using the methods described above for Error! Referencesource not found.G to give a compound of formula (IG) wherein —X— is—S—. This method is particularly useful when L₁ and R¹ are halogengroups such as for example fluoro and bromo respectively.

Alternatively, the reaction can be carried out in the presence of asuitable base such as sodium hydroxide in a suitable solvent such as amixture of ethanol and water. This method is particularly useful when L₁is a halogen group and —R¹ is CN or —CONR³R⁴, wherein R³ and R⁴ have thevalues defined for formula (IG) above.

Compounds of formula (IG) wherein —X— is —S— can also be prepared via analternative method using the intermediate of formula (VG) as illustratedbelow in Error! Reference source not found.G.

The leaving group of intermediate (VG) is displaced with a suitablethiol of formula (XIG) wherein R¹ has the values defined for formula(IG) above, in the presence of a suitable base such as potassiumcarbonate, in a suitable solvent such as DMF. The resulting intermediateof formula (IXG) wherein —X— is —S— is then deprotected as described inError! Reference source not found.G above.

The intermediate of formula (VIIIG) above (including analogs wherein L₂is introduced in place of R¹) often commercially available. This is thecase for intermediates wherein L₁ is a halogen group and R¹ (or L₂) hasthe values selected from H, methyl, halo, cyano, trifluoromethyl, NH₂,CO₂H, CONH₂, SO₂H, SO₂NHCH₃, NCOCCl₃ and NSO₂Ph.

Intermediates of formula (VIIIG) wherein R¹ is a group of formula (i)can readily be prepared via methods known in the art. We illustratebelow 3 methods for the preparation of compounds of formula (VIIIG)wherein R¹ is a group of formula (i) and -Z- has the value of a bond(Error! Reference source not found.G), —CH₂— (Error! Reference sourcenot found.G) or —O— (Error! Reference source not found.G). It will beappreciated that these methods are only illustrative as there are manyother alternative methods known in the art which can be used.

As mentioned above, intermediates of formula (VIIIG) wherein R¹ is agroup of formula (i) and -Z- is a bond can be prepared via palladiumcoupling as illustrated in Error! Reference source not found.G below.

The reaction is carried out via reaction of readily available pyridinesof formula (XIIG) wherein L₁ has the values mentioned above and L₃ is asuitable leaving group such as for example a halogen group such as bromoor chloro, with the corresponding phenylboronic acid of formula (XIIIG),in the presence of a suitable palladium catalyst such as for examplepalladium acetate, a suitable ligand such as triphenylphosphine, in asuitable solvent such as acetonitrile. Alternative palladium catalystsare known in the art, for examplebis(benzonitrile)palladium(II)dichloride can be used in the presence ofa suitable ligand such as for example bis(diphenylphosphine)butane and asuitable base such as sodium carbonate in a suitable solvent such as forexample ethanol, to give good yields of intermediate of formula (VIIIG)wherein R¹ is a group of formula (i) and -Z- is a bond.

Intermediates of formula (VIIIG) wherein R¹ is a group of formula (i)and -Z- is —CH₂— can be prepared by the method illustrated in Error!Reference source not found.G below.

Readily available pyridine compounds of formula (XIVG) wherein L₁ hasthe values mentioned above (preferably fluoro) are reacted with suitablebenzaldehydes of formula (XVG), wherein R⁵ has the value defined forformula (IG) above, in the presence of a suitable base such as forexample n-butyllithium or lithium diisopropylamide, in a suitablesolvent such as THF, to give the alcohol of formula (XVIG). Said alcoholis then reduced to give the corresponding benzyl derivative (VIIIG)wherein R¹ is a group of formula (i) and -Z- is —CH₂— via hydrogenation,in the presence of a suitable catalyst such as for example palladium oncharcoal, in a suitable solvent such as for example ethanol.

Intermediates of formula (VIIIG) wherein R¹ is a group of formula (i)and -Z- is —O— can be prepared by the method illustrated below in Error!Reference source not found.G.

Readily available pyridinols of formula (XVIIG), wherein L₁ has thevalues mentioned above react with phenylboronic acids of formula (XIIIG)in the presence of copper(II)acetate, powdered 4 Å molecular sieves, anda suitable base such as triethylamine, in a suitable solvent such as forexample dichloromethane to give intermediates of formula (VIIIG) whereinR¹ is a group of formula (i) and -Z- is —O—.

Compounds of formula (IG) wherein —X— is —O— may also be prepared byconventional chemistry techniques from the (2R) alcohol (IVG)_(a) usingstandard methods known in the art. For example as shown in Scheme 9G byreaction of said alcohol with a pyridine of the formula (XVIIIG) or theketone tautomer of this pyridine wherein R¹ has the values defined forformula (IG) above, in the presence of a suitable phosphine such astriphenyl phosphine and diethyl azodicarboxylate, using an appropriatesolvent such as THF, dimethoxyethane, (DME), or chloroform (CHCl₃), asdescribed by D. L. Comins and G. Jianhua, in Tetrahedron Letters, 1994,35 (18), pp 2819-2822. This reaction is usually carried out withinversion of the stereocentre to (2S)

As previously mentioned, compounds of formula (IG) wherein —X— is —O—may alternatively be prepared by the reaction of the (2S) alcohol (IVG)with a pyridine of the formula (VIIIG), where L₁ is preferably chloroand R¹ has the values defined for formula (IG) above, using a suitablebase such as potassium hydroxide, in a suitable solvent such as benzeneor toluene, in the presence of a suitable phase transfer catalyst suchas 18-Crown-6 as described by A. J. S. Duggan et al, in Synthesis, 1980,7, p 573.

Compounds of formula (IG) wherein —X— is —O— may alternatively beprepared by the reaction of intermediate (VG) wherein L is Br with apyridine of the formula (VIIIG) wherein -L₁ is —OAg and R¹ has thevalues defined for formula (IG) above, in a non-polar solvent such asbenzene, as described by U. Schollkopf et al, in Liebigs Ann. Chem.1972, 765, pp 153-170 and G. C. Hopkins et al, in J. Org. Chem. 1967,32, pp 4040.

It will be appreciated that compounds of Formulae (IA), (IB), (IC),(ID), (IE), (IF) and (IG) above possess one or more asymmetric carbonatoms, and that in the present invention specific individualstereoisomers are preferred. In the present specification, where astructural formula does not specify the stereochemistry at one or morechiral centres, it encompasses all possible stereoisomers and allpossible mixtures of stereoisomers (including, but not limited to,racemic mixtures), which can result from stereoisomerism at each of theone or more chiral centers.

The following examples illustrate compounds of of Formula (IA) above andmethods for their preparation.

EXAMPLE 1AN-(2-methyltropyl)-N-{(2-fluorophenyl)methyl]piperidin-4-amine fumarate

To a dry boiling tube (50 ml), under nitrogen, was addedtert-butyl-4-(2-methyl-propylamino)-piperidine-1-carboxylate (0.200 g,0.780 mmol), 2-fluorobenzaldehyde (0.087 ml, 0.102 g, 0.819 mmol), andtitanium isopropoxide (0.268 ml, 0.937 mmol) to give a yellow/orangesolution. This was heated to 90° C. for 2 hours. Solution cooled, andethanol (5 ml) added. Sodium borohydride (0.030 g, 0.780 mmol) was thenadded and allowed to stir for 2 days. Further sodium borohydride (0.300g, 7.80 mmol) was added, and after 6 hours, this was diluted withmethanol (10 ml) with stirring for 20 hours. This was concentrated invacuo, dissolved in dichloromethane (5 ml), and acetic anhydride (0.371ml, 39.00 mmol) added with stirring for 30 minutes. Solution was dilutedwith methanol (10 ml), and passed through an SCX-2 column to give an oil(0.150 g, 0.412 mmol).

The resultant oil was dissolved in dichloromethane (5 ml), andtrifluoroacetic acid (2 ml) added. Reaction was monitored by thin layerchromatography (100% ethyl acetate; reactant. r.f. 0.4, product r.f.0.0). After 2 hours, reaction was concentrated in vacuo, azeotroped withdichloromethane (c.a. 25 ml), taken up in methanol (c.a. 5 ml), andpassed through an SCX-2 column. The resultant colourless oil waspurified using reverse phase chromatography, concentrated in vacuo,taken up in 5 M hydrochloric acid (10 ml), and heated to 90° C. for 3hours. This solution was freeze dried to give an oil (0.049 g, 0.185mmol). Resultant oil was passed through an SCX-2 column, dissolved inaqueous acetonitrile (c.a. 20 ml), and fumaric acid (0.0214 g, 0.1850mmol) added. After 5 minutes, this was freeze dried to give a whitesolid (0.070 g, 0.185 mmol) as the title compound. δ_(H) (300 MHz, MeOD)7.47 (1H, t, Ar), 7.25 (1H, m, Ar), 7.13 (1H, t, Ar), 7.02 (1H, t, Ar),6.70 (2H, s, fumarate), 3.21 (2H, s, NCH2Ar), 3.45 (2H, d, CH), 2.95(2H, t, CH), 2.82 (1H, t, CH), 2.29 (2H, d, NCH2), 2.00 (2H, d, CH),1.80 (2H, t, m), 1.68 (1H, t, CH), 0.85 (6H, d, CHMe2). LCMS 12 minutegradient, Rt=1.99 mins, (M⁺+1)=265.2

EXAMPLE 2A N-(3,3-dimethylbutyl)-N-[(2-biphenyl)methyl]piperidin-4-aminefumarate

To a 100 ml round bottomed flask, under nitrogen, was added the 1,1-dimethylethyl4-[(2-bromophenylmethyl)(3,3-dimethylbutyl)amino]piperidine-1-carboxylate(0.675 g, 1.49 mmole, 1.0 eq.), phenylboronic acid (0.363 g, 2.98 mmole,2.0 eq.), dichlorobis(triphenylphosphine)palladium(II) (0.104 g, 0.15mmole, 0.1 eq.), sodium carbonate (0.158 g, 2.98 mmole, 2.0 eq.) and a1:1 mixture of tetrahydrofuran : water (50 ml). The mixture was heatedat 90° C. for two hours. The reaction mixture was allowed to cool thenpoured into diethyl ether (100 ml). This organic mixture was washed witha solution of sodium hydroxide (2M, aqueous, 80 ml) then concentrated invacuo to give a dark yellow oil (1.18 g). This oil was purified byautomated flash chromatography using an ISCO Combiflash system (SiO₂(120 g); 0-10% methanol (+5% 7M NH₃/MeOH) in dichloromethane gradientelution over 40 minutes) to give a yellow oil (0.683 g). This oil wasfurther purified by automated flash chromatography using an ISCOCombiflash system (SiO₂ (120 g); ethyl acetate gradient elution over 40minutes) to give 1,1-dimethylethyl4-[({2-biphenyl}methyl)(3,3-dimethylbutyl)amino]piperidine-1-carboxylateas a yellow oil (0.549 g, 82%). To a solution of this oil (0.549 g, 1.22mmole, 1.0 eq.) in dichloromethane (10 ml) was addedtrifluoromethanesulfonic acid (TFA) (1.36 ml, 18.27 mmole, 15 eq). Thesolution was stirred for one hour at room temperature. Solvent and TFAwere removed in vacuo. The resulting oil was taken up in methanol andloaded onto an SCX-2 (10 g) column. The column was washed with methanol(50 ml). Basic material was then eluted using 2N ammonia in methanol (50ml). Removal of solvent from the ammonia/methanol mixture under vacuum,gave a colourless oil (0.27 g). This oil was purified on the BiotageParallel Flex Purification System (UV-guided HPLC) followed by SCX-2treatment (to obtain the free base) to give a colourless oil (0.132 g).To a solution of this oil in methanol was added a solution of fumaricacid (0.044 g g, 0.38 mmole, 1 eq) in methanol. The mixture was left tostir for a couple of minutes, ethyl acetate and cyclohexane were thenadded. The resulting precipitate was collected by filtration to give thetitle compound as a white solid (0.121 g, 17%). OH (300 MHz, MeOD)7.50-7.47 (1H, m, ArH), 7.35-7.18 (7H, m, ArH), 7.10-7.07 (1H, m, ArH),6.61 (3H, s, fumarate CH), 3.58 (2H, s, CH₂Ar), 3.25-3.24 (2H, m, NCH₂),2.74 (2H, dt, NCH₂), 2.67-2.57 (1H, m, NCH), 2.34-2.29 (2H, m, NCH₂),1.65-1.45 (4H, m, CCH₂), 1.13-1.08 (2H, m, CH₂tBu), 0.70 (9H, s, CH₃);LCMS 12 min, Rt=4.3 min, (M⁺+1)=351.

EXAMPLE 3A N-(2-ethylbutyl)-N-[(2-biphenyl)methyl]piperidin-4-aminefumarate

As method previously described for Example 2A, using 1,1-dimethylethyl4-[(2-bromophenylmethyl)(2-ethylbutyl)amino]piperidine-1-carboxylate.Isolation of the fumarate salt from methanol, diethyl ether, cyclohexaneyielded the title compound as a white solid (0.238 g, 34%). OH (300 MHz,MeOD) 7.59-7.57 (1H, m, ArH), 7.45-7.27 (7H, m, ArH), 7.19-7.16 (1H, m,ArH), 6.69 (1.5H, s, fumarate CH), 3.62 (2H, s, CH₂Ar), 3.34-3.32 (2H,m, NCH₂), 2.79 (2H, dt, NCH₂), 2.66-2.57 (1H, m, NCH), 2.21 (2H, d,NCH₂), 1.64-1.50 (4H, m, CCH₂), 1.38-1.17 (5H, m, CH(CH₂Me)₂), 0.78 (6H,t, CH₃); LCMS 12 min, Rt=5.1 min, (M⁺+1)=351.

EXAMPLE 4A N-(cyclohexylmethyl)-N-[(2-biphenyl)methyl]piperidin-4-aminefumarate

(i) To a solution of cyclohexylmethylamine (0.461 g, 4.08 mmole, 1.02eq.) in 1,2-dichloroethane (10 ml) was added 1-Boc-4-piperidone (0.797 gml, 4.00 mmole, 1.0 eq.). To this was added a solution of sodiumtriacetoxyborohydride (0.865 g, 4.08 mmole, 1.02 eq.) indimethylformamide (2 ml). This mixture was left to stir under nitrogen,at room temperature, over the weekend. To the reaction mixture was thenadded water (10 ml) and the mixture stirred vigorously for severalminutes. The chlorinated organic layer was then run through ahydrophobic frit then diluted with methanol (10 ml) and loaded onto anSCX-2 (10 g) column. The column was washed with methanol (50 ml) thenbasic material eluted with 2N ammonia in methanol. The ammonia/methanolsolution was concentrated in vacuo to give a pale yellow oil (1.2 g).This was purified by automated flash chromatography using an ISCOCombiflash system (SiO₂ (40 g); 0-10% methanol in ethyl acetate gradientelution over 40 minutes) to give 1,1-dimethylethyl4-[(cyclohexylmethyl)amino]piperidine-1-carboxylate as a colourless oil(0.98 g, 83%). δ_(H) (300 MHz, CDCl₃) 4.03-4.00 (2H, m, NCH₂), 2.83-2.75(2H, m, NCH₂), 2.60-2.49 (1H, m, NCH), 2.45 (2H, d, NCH₂), 1.18-0.83(15H, m, CCH₂), 1.45 (9H, s, OC(CH₃)₃); LCMS 6 min, Rt=2.7 min,(M⁺+1)=297.

(ii) To a solution of 1,1-dimethylethyl4-[(cyclohexylmethyl)amino]piperidine-1-carboxylate (0.245 g, 0.840mmole, 1.0 eq.), 2-phenylbenzyl bromide (0.185 ml, 1.01 mmole, 1.2 eq.)in dry acetonitrile (5 ml) was added anhydrous potassium carbonate (0.19g, 1.35 mmole, 1.6 eq.). The mixture was stirred overnight at roomtemperature. The reaction mixture was concentrated under vacuum to givea white solid. The white solid was taken up in dichloromethane (10 ml)and this washed with water (10 ml). The dichloromethane layer was passedthrough a hydrophobic frit then diluted with methanol (10 ml). Thissolution was loaded onto an SCX-2 (10 g) column. The column was washedwith methanol (50 ml) then basic material was eluted using 2N ammonia inmethanol (50 ml). Concentration of the ammonia/methanol solution undervacuum yielded a colourless oil (0.344 g, 90%). To a solution of thisoil (0.344 g, 0.74 mmole, 1.0 eq.) in dichloromethane (10 ml) was addedtrifluoroacetic acid (TFA) (0.83 ml, 11.2 mmole, 15 eq). The solutionwas stirred overnight at room temperature. Solvent and TFA were removedin vacuo. The resulting oil was taken up in methanol and loaded onto anSCX-2 (10 g) column. The column was washed with methanol (50 ml). Basicmaterial was then eluted using 2N ammonia in methanol (50 ml). Removalof solvent from the ammonia/methanol mixture under vacuum, gave acolourless oil (0.298 g, 99%). The oil was taken up in methanol. To thissolution was added a solution of fumaric acid (0.095 g, 0.08 mmole, 1eq) in methanol followed by diethyl ether and cyclohexane. The resultingprecipitate was collected by filtration to give the title compound as awhite solid (0.302 g, 76 %). 8H (300 MHz, MeOD) 7.58 (1H, d, ArH),7.45-7.29 (7H, m, ArH), 7.18 (1H, d, ArH), 6.70 (2H, s, fumarate CH),3.64 (2H, s, CH₂Ar), 3.33-3.32 (2H, m, NCH₂), 2.79 (2H, dt, NCH₂),2.65-2.54 (1H, m, NCH), 2.17 (2H, d, NCH₂), 1.74-1.47 (9H, m, CCH₂),1.28-1.11 (4H, m, CH, CCH₂), 0.78-0.67 (2H, m, CH₂); LCMS 12 min, Rt=5.0min, (M⁺+1)=363.

EXAMPLE 5A N-(cyclopropylmethyl)-N-[(2-biphenyl)methyl]piperidin-4-aminefumarate

As method previously described for Example 4A, using 1,1-dimethylethyl4-[(cyclopropylmethyl)amino]piperidine-1-carboxylate and 2-phenylbenzylbromide. Isolation of the fumarate salt from methanol and diethyl etheryielded the title compound as a white solid (0.485 g, 74%). δ_(H) (300MHz, MeOD) 7.68 (1H, dd, ArH), 7.47-7.29 (7H, m, ArH), 7.21 (1H, d,ArH), 6.72 (2H, s, fumarate CH), 3.76 (2H, s, CH₂Ar), 3.38-3.34 (2H, m,NCH₂), 2.92-2.82 (3H, m, NCH, NCH₂), 2.32 (2H, d, NCH₂), 1.79-1.57 (4H,m, CCH₂), 0.77-0.66 (1H, m, CH), 0.46-0.40 (2H, m, CH₂), 0.03-0.02 (2H,m, CH₂); LCMS 12 min, Rt=3.5 min, (M⁺+1)=321.

EXAMPLE 6A N-(3-methylbutyl)-N-[(2-phenoxyphenyl)methyl]peridin-4-aminedifumarate

(i) To 10% Pd/C (1.0 g, 10% wt), under nitrogen, was added a solution ofthe 1-Boc-4-piperidone (10.0 g, 50.1 mmole, 1.0 eq.) and isoamylamine(4.46 g, 51.2 mmole, 1.02 eq.) in ethanol (60 ml). This was hydrogenatedovernight, at 60 psi using a Parr hydrogenator. The catalyst was removedby filtration through Celite. Solvent was removed under vacuum to give1,1-dimethylethyl 4-[(3-methylbutyl)amino]piperidine-1-carboxylate as acolourless, slightly cloudy, oil (13.59 g, 100%). δ_(H) (300 MHz, CDCl₃)4.05-4.02 (2H, m, NCH₂), 2.82-2.75 (2H, m, NCH₂), 2.66-2.54 (3H, m, NCH,NCH₂), 1.86-1.82 (2H, m, CCH₂), 1.62 (1H, septet, CHMe₂), 1.45 (9H, s,OC(CH₃)₃), 1.41-1.17 (4H, m, CCH₂), 0.90 (6H, d, C(CH₃)₂); LCMS 6 min,Rt =2.7 min, (M⁺+1)=271.

(ii) To a solution of 1,1-dimethylethyl4-[(3-methylbutyl)amino]piperidine-1-carboxylate in 1,2-dichloroethane(10 ml) was added 2-phenoxybenzaldehyde. To this was added a solution ofsodium triacetoxyborohydride (3.0 eq.) in dimethylformamide (2 ml). Thismixture was left to stir for 3 days under nitrogen, at room temperature.To the reaction mixture was added water (10 ml) and the mixture stirredvigorously for several minutes. The chlorinated organic layer was runthrough a hydrophobic frit to remove water, diluted with methanol (10ml) and loaded onto an SCX-2 (10 g) column. The column was washed withmethanol (50 ml) then basic material eluted with 2N ammonia in methanol.The ammonia/methanol solution was concentrated in vacuo to give1,1-dimethylethyl4-[(2-phenoxyphenylmethyl)(3-methylbutyl)amino]piperidine-1-carboxylateas a colourless oil. To a solution of this oil in dichloromethane (10ml) was added trifluoroacetic acid (TFA) (15 eq). The solution wasstirred overnight at room temperature. Solvent and TFA were removed invacuo. The resulting oil was taken up in methanol and loaded onto anSCX-2 (10 g) column. The column was washed with methanol (50 ml). Basicmaterial was then eluted using 2M ammonia in methanol (50 ml). Removalof solvent from the ammonia/methanol mixture under vacuum, gave acolourless oil. The oil was taken up in methanol. To this solution wasadded a solution of fumaric acid (1 eq) in methanol. The mixture wasleft to stir for a couple of minutes, then ethyl acetate and cyclohexanewere added. The resulting precipitate was collected by filtration togive the title compound as a white solid (0.264 g, 30%). δ_(H) (300 MHz,MeOD) 7.46 (1H, dd, ArH), 7.26-7.16 (3H, m, ArH), 7.10-7.04 (1H, m,ArH), 7.00-6.95 (1H, m, ArH), 6.86-6.79 (3H, m, ArH), 6.61 (4H, s,fumarate CH), 3.68 (2H, s, CH₂Ar), 3.33-3.28 (2H, m, NCH₂), 3.04-2.96(3H, m, NCH, NCH₂), 2.56-2.51 (2H, m, NCH₂), 1.91-1.87 (2H, m, CCH₂),1.76-1.62 (2H, m, CCH₂), 1.52-1.41 (1H, m, CH), 1.30-1.23 (2H, m, CH₂),0.74 (6H, d, CH₃); LCMS 12 min, Rt=4.2 min, (M⁺+1)=353.

EXAMPLE 7A N-(3-methylbutyl)-N-[(2-biphenyl)methyl]piperidin-4-aminedifumarate

As method previously described for Example 4A, using 1,1-dimethylethyl4-[(3-methylbutyl)amino]piperidine-1-carboxylate and 2-phenylbenzylbromide. Isolation of the fumarate salt from methanol and diethyl etheryielded the title compound as a white solid (0.239 g, 24%). 8H (300 MHz,MeOD) 7.49 (1H, dd, ArH), 7.35-7.18 (7H, m, ArH), 7.10 (1H, dd, ArH),6.61 (4H, s, fumarate CH), 3.62 (2H, s, CH₂Ar), 3.25 (2H, m, NCH₂),2.78-2.59 (3H, m, NCH, NCH₂), 2.36-2.31 (2H, m, NCH₂), 1.64-1.45 (4H, m,CCH₂), 1.42-1.31 (1H, m, CH), 1.13-1.05 (2H, m, CH₂), 0.69 (6H, d, CH₃);LCMS 12 min, Rt=4.1 min, (M⁺+1)=337.

The following examples illustrate compounds of of Formula (IB) above andmethods for their preparation.

Synthesis of Intermediates.

Preparation of (4-Benzyl-morpholin-2-yl)-phenyl-methanone

A 1600 L GL reactor under N₂ was successively loaded with2-chloroacrylonitrile (33.2 kg, 379 moles) and toluene (114 L) at 21° C.Then, N-benzylethanolamine (57 kg, 377 moles) was added and the reactionmixture was post-agitated at room temperature for about 17 h. Then, themixture was diluted with toluene (336 L), cooled down to −12.4° C. andpotassium t-butoxide (42.3 kg, 377 moles) was added in portions (10)maintaining −13.7° C.≦Tmass≦−2.8° C. The mixture was post-agitated atabout 0° C. for 2.5 h, quenched by adding ultra pure water (142.5 L)maintaining 2.1° C.≦Tmass≦8.7° C. The aqueous layer (176 kg) wasseparated after 35 minutes of post-stirring allowing the mixture toreach 15° C. and the toluene layer was washed with ultra pure water(142.5 L) and the aqueous layer (162 kg) was separated. The organiclayer was then concentrated under reduced pressure (150 mbars)maintaining Tmass≦60° C. in order to distill 162 kg of toluene. Thefiltrates were then diluted with toluene (114 L) and treated with SiO₂(Merck silica gel 60, 0.063-0.1 mm, 74.1 kg) under agitation at roomtemperature for 1.25 h. SiO₂ was filtered and rinsed with toluene (2×114L). Then, the filtrates were concentrated under reduced pressure (150mbars) maintaining Tmass≦60° C. in order to distill 351.8 kg of toluene(KF: 0.01 % w/w H₂O).

The solution of 4-Benzyl-morpholine-2-carbonitrile (169.2 kg) wasdiluted with toluene (157 L) and was cooled to 0° C. andphenylmagnesiumchloride (25 wt. % solution in THF, 213 kg, 389 moles,1.36 molar equiv.) was slowly added (over 3.5 h) to the reactionmixture, maintaining the temperature at −3° C.≦Tmass≦7° C. The reactionmixture was post-stirred for 2 hours at Tmass=0° C. Then, the quench wasperformed by adding acetic acid (8.55 L, Tmass=5→17.2° C.), poststirring 10 minutes and cooling to 5° C. before adding an aceticacid/water mixture (229 L, 33/67 v/v). During the quench, addition wasperformed at such a rate that Tmass did not exceed 20° C. (typicalTmass=4.6° C. to 10.4° C.). The mixture was post-agitated overnight atRT and the aqueous layer (285.8 kg) was extracted.

The toluene layer was cooled to 0° C. and a 5 N NaOH aqueous solution(420.1 kg) was slowly added maintaining the temperature at −2.4°C.≦Tmass≦11° C. The reaction mixture was post-stirred for 1 h and theaqueous layer (494.8 kg) was extracted. The toluene layer wasconcentrated under reduced pressure (50 mbars) maintaining Tmass≦60° C.in order to distill 356.2 kg of toluene and isopropanol (180.4 kg) wasadded. The toluene was stripped off under reduced pressure (100 mbars)maintaining Tmass≦60° C. in order to distill 186.4 kg of toluene andisopropanol (135 kg) was added again to the mixture. A last distillationof toluene was performed under reduced pressure (50 mbars) maintainingTmass≦60° C. in order to distill 131 kg of toluene and isopropanol (49.4kg) was finally added to the mixture and the solution was stirred at RTuntil crystallization (17 minutes).

Ultra pure water was added (125.4 L) and the mixture was stirredovernight at RT and cooled down to about 0° C. for 1 hour. Theprecipitate was filtered and rinsed with a cooled water/isopropanol50/50 v/v solution (76.6 kg). The wet precipitate was dried under vacuumat Tjack=35° C. for 96 hours to obtain the title compound as anoff-white powder with 59% overall yield. The title compound can beresolved by the fractional crystallisation process described above.

Preparation of (4-Benzyl-morpholin-2-yl)-(3-fluoro-phenyl)-methanone

To a solution of 4-Benzyl-morpholine-2-carbonitrile (10 g, 50 mmol) indry diethyl ether (100 ml) at −10° C. under an atmosphere of nitrogenwas added (time of addition 30 minutes) a solution of3-fluorophenylmagnesium bromide (0.5N solution in tetrahydrofuran, 120ml, 60 mmol, 1.2 equivalents, available from Aldrich Chemical Company orRieke Metals) and the reaction mixture was further stirred at −10° C.for 30 minutes. Then the reaction was allowed to warm to roomtemperature and stirred for one hour. The reaction was then cooled to 0°C. and quenched by addition of hydrochloric acid (2N aqueous solution,50 ml) and the resulting mixture was stirred for 30 minutes at 0° C.Then the solution was concentrated in vacuo and the residue was taken-upby sodium hydroxide (2N aqueous solution, 60 ml). The aqueous solutionwas extracted with diethyl ether, the organics fractions were collectedand dried (MgSO₄) and the solvent removed under reduced pressure to givethe title compound as a brown oil (15 g, 100%). FIA [M+H]+=300.1.

Preparation of 2-Chloromethyl-4-fluoro-1-methoxy-benzene a)(5-Fluoro-2-methoxy-phenyl)-methanol

To a solution of 2-Methoxy-5-fluorobenzaldehyde (11.093g, 1equiv.—available from Aldrich Chemical Company) in methanol at −10° C.under nitrogen atmosphere was added NaBH₄ (7.515 g, 2.7 equiv.)portionwise. The solution was allowed to warm to room temperature andafter 30 minutes the reaction solvent was removed under reduced pressureand replaced with dichloromethane. This solution was poured onto icewater and further extracted with dichloromethane. The organic fractionswere collected and dried (MgSO₄) and the solvent removed under reducedpressure to give the title compound as an oil (9.794 g, 87%).¹H NMR (300MHz, CDCl₃): δ 2.58 (m, 1H), 3.81 (s, 3H), 4.63 (d, 2H, J=6.3 Hz), 6.78(dd, 1H, J=8.9 and 4.3 Hz), 6.94 (td, 1H, J=8.5 and 3.1 Hz), 7.04 (dd,1H, J =8.7 and 3.1 Hz).

b) 2-Chloromethyl-4-fluoro-1-methoxy-benzene

Neat (5-Fluoro-2-methoxy-phenyl)-methanol (19.587 g, 1 equiv.) was addedto neat SOCl₂ (42.2 mL, 4.6 equiv.) at −78° C. under a nitrogenatmosphere and the solution was then allowed to warm to room temperatureand stirred until evolution of gas had ceased. An equivalent volume ofanhydrous toluene was added to the flask and the solution heated to 60°C. On cooling the reaction solution was poured onto ice water. Thetoluene layer was separated and dried (MgSO₄) and the solvent removedunder reduced pressure. The crude material was sublimed (60-80° C./0.05mBarr) to give the title compound as a white solid (13.40 g, 61%). ¹HNMR (300 MHz, CDCl₃): δ 3.87 (s, 3H), 4.60 (s, 2H), 6.79-7.20 (m, 3H).

Preparation of 1-Chloromethyl-2-isopropoxy-benzene a)(2-Isopropoxy-phenyl)-methanol

A mixture of 2-hydroxybenzyl alcohol (21.04 g, 1 equiv., available fromAldrich Chemical Company), 2-isopropyl iodide (32.3 mL, 1.9 equiv.,available from Aldrich Chemical Company) and K₂CO₃ (71.42 g, 3 equiv.)in ethanol was refluxed for 3 hours. On cooling the reaction mixture wasfiltered and the solvent removed under reduced pressure and replacedwith dichloromethane, and then filtered and the solvent removed to givethe title compound as an oil (27.751 g, 99%). ¹H NMR (300MHz, CDCl₃): δ1.37 (d, 6H, J=6.0Hz), 3.55 (bs, 1H), 4.50-4.70 (m, 3H), 6.78-6.90 (m,2H), 7.15-7.25 (m, 2H).

b) 1-Chloromethyl-2-isopropoxy-benzene

The title compound was prepared using the general procedure outlinedabove for the preparation of 2-Chloromethyl-4-fluoro-1-methoxy-benzenefollowed by the following treatment:

The crude reaction material was chromatographed on silica gel and eluted1:9 ethyl acetate/heptane prior to distillation (40-60° C./0.05 mBar).1H NMR (300 MHz, CDCl₃): δ 1.37 (d, 6H, J=6.0 Hz), 4.50-4.70 (m, 3H),6.80-7.00 (m, 2H), 7.23-7.30 (m, 2H).

Synthesis of Compounds of Formula (IB).

EXAMPLE 1B (S,R)-2-(2-Methoxy-phenyl)-1-morpholin-2-yl-1-phenyl-ethanolhydrochloride a)1-(4-Benzyl-morpholin-2-yl)-2-(2-methoxy-phenyl)-1-phenyl-ethanol

Solid magnesium turnings (9.5 g, 28 equiv.) under nitrogen atmosphere atroom temperature were stirred vigorously with a magnetic stirring barovernight. The magnesium was then covered with dry diethyl ether and tothe suspension was added 1,2-dibromoethane (50 μL). A cold bath was thenapplied followed by dropwise addition of1-chloromethyl-2-methoxy-benzene (18.18 g, 5 equiv. available fromAldrich Chemical Company) in diethyl ether (71 mL) which maintained thetemperature at up to 15° C. The resulting black suspension was stirredat room temperature for 30 minutes and cooled down at −20° C. A solutionof (4-Benzyl-morpholin-2-yl)-phenyl-methanone (4 g, 1 equiv.) in diethylether (50 mL) was then added dropwise via canula. The reaction mixturewas left to warm to room temperature over two hours and then quenched byaddition of aqueous saturated solution of NaHCO₃ (50 mL). The aqueoussolution was extracted with diethyl ether, the organic phase dried withMgSO₄, evaporated in vacuo to give 7 g of a yellow amorphous solid. Thecompound was taken without further purification in the next step. FIA[M+H]⁺=404.

b) 2-(2-Methoxy-phenyl)-1-morpholin-2-yl-1-phenyl-ethanol hydrochloride

To a solution of1-(4-Benzyl-morpholin-2-yl)-2-(2-methoxy-phenyl)-1-phenyl-ethanol (1 g,1 equiv.) in ethyl acetate (100 mL) at room temperature under nitrogenatmosphere was added ammonium formate (3.9 g, 25 equiv.) followed byaddition of palladium on charcoal (10%, 1 g.). The reaction mixture washeated to reflux for 1 hour, cooled to room temperature and thenfiltered through Celite. All volatiles were evaporated under vacuum, andthe resulting solid was purified via preparative HPLC. The isolatedwhite solid was taken up in ethanol. Hydrogen chloride was added (largeexcess of 2M solution in diethyl ether) and the mixture was stirreduntil it became a clear solution. Then all the volatiles were evaporatedin vacuo, to give 650 mg of the title compound as white solid (75%). ¹HNMR (300 MHz, DMSO D6) δ: 2.43-2.51 (m, 2H), 2.77-2.92 (m, 2H),3.15-3.23 (m, 3H), 3.41 (s, 3H), 4.10-4.19 (m, 2H), 6.66-6.72 (m, 2H),6.98-7.07 (m, 2H), 7.13-7.20 (m, 5H), 9.32 (bs, 2H). LCMS (12 minutemethod) [M+H]⁺=314@Rt 3.96 min. single major peak.

EXAMPLE 2B (S,R) 2-(2-Ethoxy-phenyl)-1-morpholin-2-yl-1-phenyl-ethanolhydrochloride a)1-(4-Benzyl-morpholin-2-yl)-2-(2-ethoxy-phenyl)-1-phenyl-ethanol

The procedure for the synthesis of example 1Ba,1-(4-Benzyl-morpholin-2-yl)-2-(2-methoxy-phenyl)-1-phenyl-ethanol, wasfollowed using commercially available 2-ethoxybenzylmagnesium bromide(available from Rieke-Metals) as starting material and makingnon-critical variations, to yield the title compound. FIA [M+H]⁺=418.

b) 2-(2-Ethoxy-phenyl)-1-morpholin-2-yl-1-phenyl-ethanol hydrochloride

The procedure for the synthesis of example 1Bb,2-(2-Methoxy-phenyl)-1-morpholin-2-yl-1-phenyl-ethanol hydrochloride wasfollowed making non-critical variations, to yield the title compound. ¹HNMR (300 MHz, DMSO D6) δ: 1.11 (t, 3H, J=6.97 Hz), 2.43-2.56 (m, 1H),2.81-2.96 (m, 2H), 3.17-3.27 (m, 3H), 3.55-3.67 (m, 2H), 3.84-3.92 (m,1H), 4.05-4.20 (m, 2H), 6.68-6.74 (m, 2H), 7.01-7.18 (m, 8H), 8.92 (bs,2H) ppm. LCMS (12 minute method) [M+H]⁺=328@Rt 4.57 min. single majorpeak.

EXAMPLE 3B S,R)2-(2-Isopropoxy-phenyl)-1-morpholin-2-yl-1-phenyl-ethanol hydrochloridea) 1-(4-Benzyl-morpholin-2-yl)-2-(2-isopropoxy-phenyl)-1-phenyl-ethanol

Solid magnesium turnings (4.6 g, 48 equiv.) under nitrogen atmosphere atroom temperature were stirred vigorously with a magnetic stirring barovernight. The magnesium was then covered with dry tetrahydrofuran. Acold bath was then applied followed by dropwise addition of1-chloromethyl-2-isopropoxy-benzene (3.0 g, 4 equiv. prepared asdescribed above) in tetrahydrofuran (40 mL). During slow addition of theelectrophile no exotherm was observed so on completion of addition 3crystals of Iodine were added to promote initiation of the reaction.After this addition the reaction temperature was allowed to spike to 50°C. then cooled rapidly to 8° C. before being left to warm to roomtemperature for one hour. The resulting black suspension was cooled downto −10° C. and a solution of (4-Benzyl-morpholin-2-yl)-phenyl-methanone(1.2 g, 1 equiv.) in tetrahydrofuran (10 mL) was then added dropwise.The reaction mixture was left to warm to room temperature over thirtyminutes and then quenched by addition of aqueous saturated solution ofNaHCO₃ (50 mL) prior to filtration through Celite. The aqueous solutionwas extracted with diethyl ether, the organic phase dried with MgSO₄,evaporated in vacuo to give 3 g of a yellow amorphous solid. Thecompound was taken without further purification in the next step. LCMS(6 minutes method) [M+H]⁺=432@Rt 3.25 min. major peak.

b) 2-(2-Isopropoxy-phenyl)-1-morpholin-2-yl-1-phenyl-ethanolhydrochloride

The procedure for the synthesis of example 1Bb,2-(2-Methoxy-phenyl)-1-morpholin-2-yl-1-phenyl-ethanol hydrochloride wasfollowed making non-critical variations, to yield the title compound. ¹HNMR (300 MHz, MeOH D3) δ: 1.12-1.16 (m, 6H), 2.51-2.55 (m, 1H),2.89-3.14 (m, 4H), 3.56-3.60 (m, 1H), 3.82-3.92 (m, 1H), 3.99-4.03 (m,1H), 4.17-4.22 (m, 1H), 4.36-4.44 (m, 1H), 6.50-6.55 (m, 1H), 6.66-6.73(m, 2H), 6.92-6.98 (m, 1H), 7.07-7.20 (m, 5H) ppm. LCMS (12 minutesmethod) [M+H]⁺=342@Rt 4.90 min. major peak.

EXAMPLE 4B (S,R)1-(3-Fluoro-phenyl)-2-(2-methoxy-phenyl)-1-morpholin-2-yl-ethanolhydrochloride a)1-(4-Benzyl-morpholin-2-yl)-1-(3-fluoro-phenyl)-2-(2-methoxy-phenyl)-ethanol

A magnetically stirred 0.25M tetrahydrofuran solution of commerciallyavailable 2-methoxybenzylmagnesium bromide (available from Rieke-Metals)(80 ml, 3equiv.) under nitrogen atmosphere was cooled to −10° C. and tothis was added neat(4-Benzyl-morpholin-2-yl)-1-(3-fluoro-phenyl)-methanone (2.1 g, 1equiv.). The solution was allowed to warm to room temperature andreaction progress followed using mass spectrometry. After 1.5 hours2-methoxybenzylmagnesium bromide solution (14 ml, 0.5 equiv.) was againadded to the reaction and after a further 0.5 hours an aqueous saturatedsolution of NaHCO₃ (50 mL) was added to halt the reaction. The aqueoussolution was extracted with diethyl ether, the organic phase dried withMgSO₄, evaporated in vacuo to give 2.8 g of a yellow amorphous solid.The compound was taken without further purification in the next step.LCMS (6 minutes method) [M+H]⁺=422@Rt 3.03 and 2.86 min. major peaks.

b)(S,R)-1-(3-Fluoro-phenyl)-2-(2-methoxy-phenyl)-1-morpholin-2-yl-ethanolhydrochloride

To a solution of1-(4-Benzyl-morpholin-2-yl)-1-(3-fluoro-phenyl)-2-(2-methoxy-phenyl)-ethanol(2.8 g, 1 equiv.) in ethyl acetate (100 mL) at room temperature undernitrogen atmosphere was added ammonium formate (4.3 g, 10 equiv.)followed by addition of palladium on charcoal (10%, 2.7 g.). Thereaction mixture was heated to reflux for 1 hour, cooled to roomtemperature and then filtered through Celite. All volatiles wereevaporated under vacuum, and the resulting solid was purified viapreparative HPLC to give the desired diastereoisomers. The activeenantiomer was obtained after a further preparative chiral HPLCseparation. The active enantiomer, a white solid, was next taken up inethanol and hydrogen chloride was added (large excess of 2M solution indiethyl ether) and the mixture was stirred until it became a clearsolution. Then all the volatiles were evaporated in vacuo, to give 447mg of the title compound as white solid. ¹H NMR (300 MHz, DMSO D6) δ:2.49-2.53 (m, 1H), 2.80-2.93 (m, 2H), 3.12-3.33 (m, 4H), 3.41 (s, 3H),3.85-3.92 (m, 1H), 4.07-4.20 (m, 2H), 6.70-6.75 (m, 2H), 6.92-7.10 (m,5H), 7.20-7.27 (m, 1H), 9.08 (bs, 2H). LCMS (12 minutes method)[M+H]⁺=332. Rt 4.11 min.

EXAMPLE 5B (S,R)1-Morpholin-2-yl-1-phenyl-2-(2-trifluoromethoxy-phenyl)-ethanolhydrochloride a)1-(4-Benzyl-morpholin-2-yl)-1-phenyl-2-(2-trifluoromethoxy-phenyl)-ethanol

Magnesium turnings (24.2 g, 0.935 mole, 2 eq.) and diethyl ether (300ml) were loaded in a reactor under N₂. A solution of2-trifluoromethoxybenzyl bromide (165 g, 0.647 mole, 1.3 eq.) in diethylether (300 ml) was loaded in an addition funnel. Iodine crystals and asmall amount of the 2-trifluoromethoxybenzyl bromide solution were addedand the reaction mixture was stirred to initiate the reaction. Theremainder of the 2-trifluoromethoxybenzyl bromide solution was thenadded drop-wise maintaining the temperature of the reaction mixturebelow 35° C. The mixture was stirred for another 5 minutes at 23° C.after completion of the addition. A solution of(4-Benzyl-morpholin-2-yl)-phenyl-methanone (140 g, 0.498 mole) indiethyl ether (2.1 L) was added drop-wise, maintaining the temperatureof the reaction mixture below 25° C. The solution obtained was stirredfor 1 hour at 20° C. The reaction mixture was quenched through theaddition of a saturated aqueous NaHCO₃ solution (700 ml) and water (700ml). The solids were filtered and washed with diethyl ether (200 ml).The filtrates were loaded into a separation funnel and the layers wereseparated. The aqueous layer was extracted with diethyl ether (1 L). Theorganic layers were combined and the filtrates were concentrated undervacuum to about 2 liters. The solution was dried over MgSO₄, filteredand the filter cake was washed with diethyl ether (200 ml). The filtratewas concentrated under vacuum to orange oil. The residue was twicedissolved in toluene (500 ml) and concentrated to a solid product. Theyield of crude title compound was 235 g (103%). ¹H-NMR (CDCI₃):6.80-7.07 ppm, 11 H, mp; 7.04-7.01 ppm, 1H, mp; 7.01-6.86 ppm, 1H, dt;6.84-6.80 ppm, 1H, d; 3.98-4.03 ppm, 1H, dt; 3.86-3.89 ppm, 1H, dd;3.70-3.60 ppm, 1H, dt; 3.52-3.58 ppm, 1H, d; 3.37-3.42 ppm, 1H, d;3.13-3.37 ppm, 1H, d; 3.05-3.08 ppm, 1H, d; 2.44-2.45 ppm, 1H, d;2.30-2.00 ppm, 3H, mp.

b) (S,R) 1-Morpholin-2-yl-1-phenyl-2-(2-trifluoromethoxy-phenyl)-ethanolhydrochloride

A stainless steel Buchi hydrogenation reactor was loaded with1-(4-Benzyl-morpholin-2-yl)-1-phenyl-2-(2-trifluoromethoxy-phenyl)-ethanol(230 g, 0.503 mole), methanol (1 L), a suspension of Pd/C (10%, 46 g,20% loading) in methanol (500 ml), and methanol (500 ml) from equipmentrinses. A solution of HCl in ethanol (1.6N, 460 ml, 0.736 mole, 1.5 eq.)was added and the reactor was pressurized with H₂ (3 Bar). The reactionmixture was heated to 40° C. and stirred for 3 hours. The reactionmixture was cooled to 20° C. and flushed with N₂. The catalyst wasfiltered off and washed with methanol (0.5 L). The filtrates wereconcentrated under vacuum to a yellow solid. The yield of crude titlecompound was 198 g (97.5%). A reactor was loaded with crude titlecompound (190 g, 0.47 mole) and toluene (6.65 L) under N₂. Thesuspension was heated under reflux and toluene (150 ml) was added untilall solid dissolved. The solution was stirred for 15 minutes more underreflux and then cooled slowly to 20° C. The suspension was stirred for 1hour at 20° C. The solid was filtered, washed with toluene (680 ml), anddried at 40° C. under vacuum. The yield of pure anhydrous title compoundwas 158.5 g (83.4%).

Alternatively, the following method can be used. In a glass-linednitrogen purged hydrogenator are charged1-(4-Benzyl-morpholin-2-yl)-1-phenyl-2-(2-trifluoromethoxy-phenyl)-ethanolhydrochloride (150 g, 303.7 mmol), demineralized water (352 mL), i-PrOH(375 mL) and 5% Pd/C (30 g, 50% water, Johnson & Matthey type 440). Theheterogeneous reaction mixture was then purged 5 times with 25 psinitrogen then purged 5 times with 50 psi hydrogen, and the hydrogenationwas performed at RT. The initial Tmass was 22° C. and the maximum Tmassduring the hydrogenation was 23° C. The reactor was stirred vigorously.In-process analysis after 2 hours indicated complete hydrogenolysis. Thehydrogenation was stopped after 3 hours. The nitrogen purged reactionmixture was then filtered at RT through an hyflo filter (56 g),impregnated beforehand with 75 mL of a 50/50 v/v isopropanol/watermixture and washed with 300 mL of a 50/50 v/v isopropanol/water mixture.The filtrates were stored overnight at RT. The filtrates wereconcentrated at 40-50° C. under reduced pressure (typical 622 gdistilled). The reaction mixture was cooled to RT and post-agitated.After 3 hours, 1 mL of the solution was taken and cooled to 0° C. toinitiate crystallization. These seeds were added to the reaction mixtureand precipitation was observed within a few minutes. The mixture waspost-agitated at RT for 2 hours. The crystals were filtered and rinsedwith H₂O (30 mL). Then, the precipitate was dried under reduced pressure(400 mmHg) with a nitrogen flow (0.1 bar) for 4 hours affording thetitle compound as the hydrate polymorph (103.5 g, 81% yield).

EXAMPLE 6B (S,R) 2-Biphenyl-2-yl-1-morpholin-2-yl-1-phen-1-ethanolhydrochloride a)1-(4-Benzyl-morpholin-2-yl)-2-biphenyl-2-yl-1-phenyl-ethanol

1-(4-Benzyl-morpholin-2-yl)-2-(2-bromo-phenyl)-1-phenyl-ethanol (0.50 g,1.0 equiv. prepared according to Example 15Ba below) and phenylboronicacid (0.402 g, 3.0 equiv., available from Aldrich Chemical Company) weresuspended in a mixture ethanol/water (2/1, 7.5 mL) and Pd(Ph₃)₄ (0.022g, 0.04 equiv.), then K₂CO₃ (0.654 g, 4.30 equiv.) were added. Themixture was heated to 80° C. under nitrogen atmosphere. After 16 hours,the reaction was cooled down to room temperature and filtered throughCelite, then extracted with ethyl acetate. The organic layers werecombined, dried with MgSO₄, filtered and concentrated in vacuo yieldinga yellow oil, which was purified by column chromatography on silica gel(10% EtOAc:Hexane) to give 0.491 g (98%) of the title compound as awhite solid.

b) (S,R) 2-Biphenyl-2-yl-1-morpholin-2-yl-1-phenyl-ethanol hydrochloride

The procedure for the synthesis of example 1Bb,2-(2-methoxy-phenyl)-1-morpholin-2-yl-1-phenyl-ethanol hydrochloride,was followed making non-critical variations, to yield the titlecompound.¹H NMR (300 MHz, DMSO D6) δ: 2.16-2.20 (m, 1H), 2.54-2.62 (m,1H), 2.67-2.76 (m, 1H), 2.85-2.89 (m, 1H), 3.24 (s, 2H), 3.61-3.69 (m,2H), 3.93-3.98 (m, 1H), 5.14 (bs, 1H), 6.80-6.92 (m, 5H), 7.04-7.17 (m,5H), 7.27-7.30 (m, 3H), 7.36-7.39 (m, 1H). LCMS (12 minutes method)[M+H]⁺=360@Rt 5.15 min. single major peak.

EXAMPLE 7B (S,R) 2-(2-Chloro-phenyl)-1-mortholin-2-yl-1-phenyl-ethanolhydrochloride a)1-(4-Benzyl-morpholin-2-yl)-2-(2-chloro-phenyl)-1-phenyl-ethanol

The procedure for the synthesis of example 1Ba,1-(4-Benzyl-morpholin-2-yl)-2-(2-methoxy-phenyl)-1-phenyl-ethanol, wasfollowed using 2-chlorobenzyl chloride (available from Aldrich ChemicalCompany) as starting material and making non-critical variations, toyield the title compound. FIA [M+H]⁺=408 and 410.

b) (S,R) 2-(2-Chloro-phenyl)-1-morpholin-2-yl-1-phenyl-ethanolhydrochloride

The procedure for the synthesis of example 5Bb, (S, R)1-Morpholin-2-yl-1-phenyl-2-(2-trifluoromethoxy-phenyl)-ethanolhydrochloride, was followed making non-critical variations, to yield thetitle compound.¹H NMR (300 MHz, DMSO D6) δ: 2.45-2.54 (m, 1H), 2.84-2.93(m, 2H), 3.17-3.22 (m, 1H), 3.33-3.38 (m, 3H), 3.89-3.97 (m, 1H),4.14-4.18 (m, 2H), 7.06-7.11 (m, 2H), 7.15-7.26 (m, 7H), 9.24 (bs, 2H)ppm. LCMS (12 minutes method) [M+H]⁺=318-320@Rt 4.36 min. single peak.

EXAMPLE 8B (S,R)2-(5-Fluoro-2-methoxy-phenyl)-1-morpholin-2-yl-1-phenyl-ethanolhydrochloride a)1-(4-Benzyl-morpholin-2-yl)-2-(5-fluoro-2-methoxy-phenyl)-1-phenyl-ethanol

Magnesium turnings (21.6 g, 0.888 mole, 2 eq.) and diethyl ether (300ml) were loaded in a reactor under N₂. A solution of5-fluoro-2-methoxybenzyl chloride (116 g, 0.664 mole, 1.5 eq.) indiethyl ether (200 ml) was loaded in an addition funnel. Iodine crystalsand a small amount of the 5-fluoro-2-methoxybenzyl chloride solutionwere added and the reaction mixture was stirred to initiate thereaction. The remainder of the 5-fluoro-2 methoxybenzyl chloridesolution was then added drop-wise maintaining the temperature of thereaction mixture below 28° C. The mixture was stirred for another 5minutes at 19° C. after completion of the addition and a whitesuspension was formed. A solution of(4-Benzyl-morpholin-2-yl)-phenyl-methanone (125 g, 0.444 mole) indiethyl ether (1.8 L) was added drop-wise, maintaining the temperatureof the reaction mixture below 25° C. The suspension obtained was stirredfor 2 hours. The reaction mixture was quenched through the addition of asaturated aqueous NaHCO₃ solution (625 ml) and water (500 ml),maintaining the temperature below 20° C. The mixture was stirred for 30minutes and the solids were filtered, washed with water (125 ml) anddiethyl ether (200 ml). The filtrates were loaded into a separationtunnel and the layers were separated. The aqueous layer was extractedwith diethyl ether (1 L). The organic layers were combined and driedover MgSO₄, filtered and the filter cake was washed with diethyl ether(100 ml). The filtrates were concentrated under vacuum. The yield oftitle compound was 201 g as a yellow solid (107%). Title compound (200g, 0.474 mole) was then suspended in isopropanol (400 ml) under N₂. Thesuspension was heated under reflux until all solids were dissolved. Thesolution is allowed to cool to 20° C. over 4 hours under stirring. Thesolid is filtered, washed with isopropanol (100 ml) and dried at 40° C.under vacuum. The yield of pure title compound is 158 g (79%). ¹H-NMR(CDCl₃): 6.99-7.26 ppm, 10H, mp; 6.60-6.71 ppm, 1H, dt; 6.49-6.60 ppm,1H, dd; 6.31-6.44 ppm, 1H, dd; 3.92-4.01 ppm, 1H, dt; 3.80-3.90 ppm, 1H,dd; 3.64-3.73 ppm, 1H, dd; 3.59-3.64 ppm, 1H, d; 3.52-3.59 ppm, 3+1 H,2s; 3.37-3.45 ppm, 1H, d; 3.07-3.17 ppm, 1H, d; 2.84-2.92 ppm, 1H, d;2.43-2.53 ppm, 1H, d; 2.20-2.28 ppm, 1H, d; 1.98-2.11 ppm, 2H, mp.

b) (S,R) 2-(5-Fluoro-2-methoxy-phenyl)-1-morpholin-2-yl-1-phenyl-ethanolhydrochloride

A glass hydrogenation flask was loaded with methanol (1.55 L), Pd/C(10%, 31 g, 20% loading),1-(4-benzyl-morpholin-2-yl)-2-(5-fluoro-2-methoxy-phenyl)-1-phenyl-ethanol(155 g, 0.368 mole) and a solution of HCl in ethanol (2.5N, 233 ml,0.582 mole, 1.6 eq.). The reactor was mounted on a Parr instrument andpressurized with H₂ (49 Psi). The reaction mixture was shaken overnightbetween 20° C. and 15° C. The catalyst was filtered off and washed withmethanol (0.5 L). The filtrates were concentrated under vacuum. Theyield of crude title compound was 109.5 g (81%). The catalyst was washedagain with methanol (2×500 ml). The filtrates were combined andconcentrated under vacuum. The yield of the second crop of crude titlecompound was 21.7 g (16%). A reactor was loaded with crude titlecompound (131 g, 0.356 mole) and isopropanol (1,3 L) under N₂. Thesuspension was heated under reflux for 4 hours. The mixture was cooledto 20° C. and the solid was filtered, washed with isopropanol (130 ml),and dried at 50° C. under vacuum. The yield of pure title compound was115.9 g (88.5% yield).

EXAMPLE 9B (S,R)1-Morpholin-2-yl-1-phenyl-2-(2-trifluoromethylsulfanyl-phenyl)-ethanolacetate a)1-(4-Benzyl-morpholin-2-yl)-1-phenyl-2-(2-trifluoromethylsulfanyl-phenyl)-ethanol

The procedure for the synthesis of example 1Ba,1-(4-benzyl-morpholin-2-yl)-2-(2-methoxy-phenyl)-1-phenyl-ethanol, wasfollowed using 1-bromomethyl-2-trifluoromethylsulfanyl-benzene(available from Fluorochem Ltd.) as starting material and makingnon-critical variations, to yield the title compound. ¹H NMR (300 MHz,CDCl₃) δ: 2.05-2.33 (m, 3H), 2.49-2.65 (m, 1H), 3.10-3.35 (m, 2H),3.43-3.55 (m, 1H), 3.67-3.89 (m, 2H), 3.91-4.08 (m, 2H), 4.09-4.22 (m,1H), 6.91-7.05 (m, 1H), 7.10-7.42 (m, 12H), 7.50-7.63 (m, 1H) ppm.

b) (S, R)1-Morpholin-2-yl-1-phenyl-2-(2-trifluoromethylsulfanyl-phenyl)-ethanolacetate

To a solution of1-(4-benzyl-morpholin-2-yl)-1-phenyl-2-(2-trifluoromethylsulfanyl-phenyl)-ethanol(218 mg g, 1 equiv.) and solid supported Hunig's base (available fromArgonaut, 1 g, 5 equiv.) in dry tetrahydrofuran (4 mL) at 0° C. undernitrogen atmosphere was added ACE-Cl (502 μL, 10 equiv.). The reactionmixture was left to warm to room temperature for 48 hours. All volatileswere evaporated under vacuum, and the resulting solid was taken-up withmethanol (50 mL) and stirred at room temperature overnight. The solutionwas filtered through acid ion exchange column and the required fractionsevaporated to dryness. The resulting solid was purified via preparativeHPLC to give 62 mg of the title compound as a colourless oil. ¹H NMR(300MHz, CDCl₃) δ: 2.01 (s, 3H), 2.43-2.47 (m, 1H), 2.63-2.70 (m, 1H),2.81-2.94 (m, 2H), 3.24 (d, 1H, J=13.57 Hz), 3.85-3.96 (m, 2H),4.01-4.05 (m, 1H), 4.09-4.13 (m, 1H), 4.45 (bs, 4H), 6.90-6.93 (m, 1H),7.13-7.26 (m, 7H), 7.55-7.58 (m, 1H), ppm. LCMS (12 minute method)[M+H]⁺=384@Rt 5.13 min. single peak.

EXAMPLE 10B (S,R)1-Morpholin-2-yl-1-phenyl-2-(2-trifluoromethyl-phenyl)-ethanol a)4-Benzyl-2-(2-phenyl-oxiranyl)-morpholine

To a mixture of trimethylsulfoxonium iodide (783 mg, 1 equiv.) andsodium hydride (142 mg, 1 equiv.) in dimethylformamide (17 mL) at 0° C.under nitrogen atmosphere was added dimethylsulfoxide (251 μL, 1 equiv.)and the resulting suspension was stirred for 30 minutes. A solution of(4-Benzyl-morpholin-2-yl)-phenyl-methanone (1 g, 1 equiv.) indimethylformamide (10 mL) was then added dropwise. Stirring wascontinued for 30 minutes and the reaction was stopped by addition ofwater (50 mL). The aqueous solution was extracted with diethyl ether,the organic phase dried with MgSO₄, and evaporated in vacuo. The crudematerial was purified using a column chromatography on silica geleluting with a mixture of ethyl acetate/heptane (20/80) to give 825 mgof the title compound as a colourless oil (78%), mixture of twodiastereoisomers. LCMS (6 minute method) [M+H]⁺=296@Rt 1.88 min. singlepeak.

b)1-(4-Benzyl-morpholin-2-yl)-1-phenyl-2-(2-trifluoromethyl-phenyl)-ethanol

To a suspension of magnesium turnings in tetrahydrofuran (2 mL) at roomtemperature under nitrogen atmosphere was added a solution of1-bromo-2-trifluoromethyl-benzene (7.6 g, 5 equiv., available fromAcros) in tetrahydrofuran (32 mL) and the mixture was stirred for anhour. The solution was cooled to −78° C. and copper iodide (646 mg) wasadded followed by dropwise addition of a solution of4-Benzyl-2-(2-phenyl-oxiranyl)-morpholine (2g, 1 equiv.) intetrahydrofuran (10 mL). The resulting mixture was warmed to roomtemperature over 2 hours and then treated with water (10 mL). Thesolution was extracted with diethyl ether, the organic phase dried withMgSO₄, and evaporated in vacuo. The crude material was purified using acolumn chromatography on silica gel eluting with a mixture of ethylacetate/heptane (10/90) to give 352 mg of the title compound as acolourless oil (12%). LCMS (6 minutes method) [M+H]⁺=442@Rt 3.05 min.major peak.

c) (S,R) 1-Morpholin-2-yl-1-phenyl-2-(2-trifluoromethyl-phenyl)-ethanol

To a solution of1-(4-Benzyl-morpholin-2-yl)-1-phenyl-2-(2-trifluoromethyl-phenyl)-ethanol(352 mg, 1 equiv.) in ethanol (15 mL) at room temperature under nitrogenatmosphere was added ammonium formate (507 mg g, 10 equiv.) followed byaddition of palladium on charcoal (10%, 355 mg.). The reaction mixturewas heated to reflux for 1 hour, cooled to room temperature and thenfiltered through Celite. All volatiles were evaporated under vacuum togive 265 mg of the title compound as white solid (94%). The enantiomericmixture was resolved using chiral HPLC, to give the title compound as asingle enantiomer. ¹H NMR (300 MHz, CDCl₃) δ: 2.25-2.30 (m, 1H),2.56-2.64 (m, 1H), 2.75-2.87 (m, 2H), 3.18 (d, 1H, J=14.88 Hz),3.71-3.81 (m, 2H), 3.89 (d, 1H, J=14.88 Hz), 4.02-4.05 (m, 1H),6.83-6.86 (m, 1H), 7.09-7.34 (m, 7H), 7.53-7.55 (m, 1H) ppm. LCMS (12minute method) [M+H]⁺=352@Rt 4.73 min. single peak.

EXAMPLE 11B (S,R)2-(2-Chloro-phenyl)-1-(3-fluoro-phenyl)-1-morpholin-2-yl-ethanolhydrochloride a)1-(4-Benzyl-morpholin-2-yl)-2-(2-chloro-phenyl)-1-(3-fluoro-phenyl)-ethanol

The procedure for the synthesis of 4Ba,1-(4-Benzyl-morpholin-2-yl)-1-(3-fluoro-phenyl)-2-(2-methoxy-phenyl)-ethanolwas followed using 2-chorobenzyl chloride (available from AldrichChemical Company) as starting material, and making non-criticalvariations, to yield the title compound which was taken without furtherpurification in the next step. LCMS (6 minutes method) [M+H]⁺=426@Rt2.85 min. major peak.

b) (S,R)2-(2-Chloro-phenyl)-1-(3-fluoro-phenyl)-1-morpholin-2-yl-ethanolhydrochloride

To a solution of1-(4-Benzyl-morpholine-2-yl)-2-(2-chloro-phenyl)-1-(3-fluoro-phenyl)-ethanol.(3.2 g, 1 equiv.) in dry 1,2-dichloroethane (40 mL) under nitrogenatmosphere was added ACE-Cl (20.33 g, 5 equiv.). The reaction mixturewas stirred at room temperature overnight then refluxed untilcompletion. All volatiles were evaporated under vacuum, and theresulting residue redissolved in acetonitrile. This solution wasfiltered through an ion exchange column and the filtrate taken-up withmethanol (50 mL) and refluxed for 3h. The solution was again filteredthrough acid ion exchange column and the required fractions evaporatedto dryness. The resulting solid was next purified via preparative HPLCfollowed by chiral HPLC. The purified active enantiomer was taken up inethanol and hydrogen chloride was added (large excess of 2M solution indiethyl ether) and the mixture stirred. Then all the volatiles wereevaporated in vacuo, to give 519 mg of the title compound as a whitesolid (18%). ¹H NMR (300 MHz, DMSO D6) δ: 2.43-2.54 (m, 1H), 2.81-2.95(m, 2H), 3.16-3.23 (m, 1H), 3.30-3.44 (m, 2H), 3.54 (bs, 1H), 3.92-4.00(m, 1H), 4.15-4.23 (m, 2H), 6.96-7.29 (m, 8H), 9.32-9.45 (m, 2H). LCMS(12 minute method) [M+H]⁺=336.

EXAMPLE 12B (S,R) 1-Morpholin-2-yl-1-phenyl-2-o-tolyl-ethanolhydrochloride a) 1-(4-Benzyl-morpholin-2-yl)-1-phenyl-2-o-tolyl-ethanol

The procedure for the synthesis of example 1Ba,1-(4-benzyl-morpholin-2-yl)-2-(2-methoxy-phenyl)-1-phenyl-ethanol, wasfollowed using commercially available 2-methylbenzylmagnesium bromide(available from Rieke-Metals) as starting material and makingnon-critical variations, to yield the title compound. FIA [M+H]⁺=388.

b) (S,R) 1-Morpholin-2-yl-1-phenyl-2-o-tolyl-ethanol hydrochloride

The procedure for the synthesis of example 1Bb,2-(2-methoxy-phenyl)-1-morpholin-2-yl-1-phenyl-ethanol hydrochloride wasfollowed making non-critical variations, to yield the title compound. ¹HNMR (300 MHz, DMSO D6) δ: 1.62 (s, 3H), 2.40-2.58 (m, 1H), 2.78-3.01 (m,2H), 3.03-3.09 (m, 1H), 3.15-3.31 (m, 2H), 3.90-4.05 (m, 1H), 4.15-4.25(m, 2H), 6.89-7.28 (m, 9H), 9.21-9.55 (m, 2H). LCMS (12 minute method)[M+H]⁺=298 single peak.

EXAMPLE 13B (S,R) 1-Morpholin-2-yl-1,2-diphenyl-ethanol hydrochloride a)1-(4-Benzyl-morpholin-2-yl)-1,2-diphenyl-ethanol

The procedure for the synthesis of example 1Ba,1-(4-benzyl-morpholin-2-yl)-2-(2-methoxy-phenyl)-1-phenyl-ethanol, wasfollowed using commercially available benzylmagnesium bromide (availablefrom TCI America) as starting material and making non-criticalvariations, to yield the title compound. LCMS [M+H]⁺=374.1 major singlepeak@3.82 min.

b) (S,R) 1-Morpholin-2-yl-1,2-diphenyl-ethanol hydrochloride

The procedure for the synthesis of example 1Bb,2-(2-methoxy-phenyl)-1-morpholin-2-yl-1-phenyl-ethanol hydrochloride wasfollowed making non-critical variations, to yield the title compound. ¹HNMR (300 MHz, CDDl₃) δ: 2.36-2.41 (m, 1H), 2.64-2.71 (m, 1H), 2.78-2.91(m, 3H), 3.16-3.32 (m, 2H), 3.73-3.82 (m, 2H), 4.08-4.11 (m, 1H),6.80-6.83 (m, 2H), 7.07-7.12 (m, 3H), 7.16-7.27 (m, 6H). LCMS[M+H]⁺=284.1 single peak@3.82 minutes.

EXAMPLE 14B (S,R) 2-(2-Fluoro-phenyl)-1-morpholin-2-yl-1-phenyl-ethanolhydrochloride a)1-(4-Benzyl-morpholin-2-yl)-2-(2-fluoro-phenyl)-1-phenyl-ethanol

The procedure for the synthesis of example 1Ba,1-(4-benzyl-morpholin-2-yl)-2-(2-methoxy-phenyl)-1-phenyl-ethanol, wasfollowed using commercially available 2-fluoro-benzylmagnesium chloride(available from Rieke Metals) as starting material and makingnon-critical variations, to yield the title compound. FIA [M+H]⁺=392.1.

b) (S,R) 2-(2-Fluoro-phenyl)-1-morpholin-2-yl-1-phenyl-ethanolhydrochloride

The procedure for the synthesis of example 1Bb,2-(2-methoxy-phenyl)-1-morpholin-2-yl-1-phenyl-ethanol hydrochloride wasfollowed making non-critical variations, to yield the title compound. ¹HNMR (300 MHz, DMSO D6) δ: 2.40-2.56 (m, 1H), 2.78-2.97 (m, 2H),3.17-3.29 (m, 3H), 3.89-3.96 (m, 1H), 4.14-4.19 (m, 2H), 5.47 (bs, 1H),6.82-6.94 (m, 2H), 7.01-7.25 (m, 7H), 9.28-9.38 (m, 2H). LCMS[M+H]⁺=302.1 single major peak (3.82 minutes.

EXAMPLE 15B (S,R) 2-(2-bromo-phenyl)-1-phenyl-1-morpholin-2-yl-ethanola) 1-(4-Benzyl-morpholin-2-yl)-2-(2-bromo-phenyl)-1-phenyl-ethanol

The procedure for the synthesis of example 1Ba,1-(4-Benzyl-morpholin-2-yl)-2-(2-methoxy-phenyl)-1-phenyl-ethanol, wasfollowed using commercially available 2-bromobenzylmagnesium bromide(available from Rieke-Metals) as starting material and makingnon-critical variations, to yield the title compound. FIA[M+H]⁺=452/454.

b) (S,R) 1-Morpholin-2-yl-2-(2-bromo-phenyl)-1-phenyl-ethanol

The procedure for the synthesis of example 5Bb, (S,R)1-Morpholin-2-yl-1-phenyl-2-(2-trifluoromethoxy-phenyl)-ethanol, wasfollowed making non-critical variations, to yield the title compound.¹HNMR (300 MHz, CDCl₃) δ: 2.64-2.68 (m, 1H), 3.02-3.21 (m, 2H), 3.27-3.33(m, 3H), 3.45-3.50 (m, 1H), 3.63-3.68 (m, 1H), 3.99-4.09 (m, 1H),4.20-4.24 (m, 1H), 4.29-4.34 (m, 1H), 4.87 (s, 1H), 6.98-7.21 (m, 2H),7.24-7.59 (m, 7H) ppm. LCMS (6 minutes method) [M+H]⁺=362.3@Rt 2.85 min.single peak.

EXAMPLE 16B (S,R)2-(2′-chlor[1-1′biphenyl]-2-yl)-1-morpholin-2-yl-1-phenyl-ethanolhydrochloride a)2-(2′-chloro[1-1′biphenyl]-2-yl)-1-phenyl-1-[4-(phenylmethyl)morpholin-2-yl]ethanol

The procedure for the synthesis of example 6Ba, was followed using2-chloro phenyl boronic acid (available from Aldrich Chemical Company)as starting material and making non-critical variations, to yield thetitle compound. FIA [M+H]⁺=485

b) (S,R)2-(2′-chloro[1-1′biphenyl]-2-yl)-1-morpholin-2-yl-1-phenyl-ethanolhydrochloride

The procedure for the synthesis of example 6Bb, was followed makingnon-critical variations, to yield the title compound. ¹H NMR (300 MHz,CDCl₃) δ: 2.10-2.21 (m, 1H), 2.57-2.65 (m, 1H), 2.62-2.75 (m, 1H),2.83-2.87 (m, 1H), 3.20 (s, 2H), 3.63-3.70 (m, 2H), 3.95-3.97 (m, 1H),5.12 (bs, 1H), 6.80-6.92 (m, 5H), 7.04-7.17 (m, 5H), 7.27-7.37 (m, 3H).LCMS (12 minutes method) [M+H]⁺=393@Rt 4.75 min. single major peak.

EXAMPLE 17B 4-Fluoro-2-(2-morpholin-2-yl-2-phenylpropyl)phenolhydrochloride a) 4-Fluoro-2-(2-morpholin-2-yl-2-phenylpropyl)phenolhydrochloride

Sodium thiomethoxide (13 eq, 186 mg) was added at once to a solution of2-{2-[5-fluoro-2-(methyloxy)phenyl]-1-methyl-1-phenylethyl}morpholinehydrochloride (75.2 mg, 0.204 mmol, synthesized as described in Example8 above) in anydrous DMF (3 ml) in a microwave vessel. Upon addition,the reaction vessel was sealed and heated up in a CEM-Discoverymicrowave at 150 Watts, reaching 110° C. in 5 minutes and maintainingthis temperature 6 minutes. The reaction vessel was cooled to roomtemperature and the reaction mixture taken into methanol (5 ml) andpurified by SCX-2 chromatography to obtain the free base as clear oil(50 mg). The hydrochloride salt was obtained following generalprocedures as a white solid (52 mg, 72% after salt formation.). MW353.83; C₁₈H₂₂NO₃FCl; ¹H NMR (CD₃OD): 7.29-7.26 (2H, m), 7.20-7.08 (2H,m), 6.53-6.50 (2H, m), 6.30-6.26 (1H, m), 4.18 (1H, dd, 12.6 Hz, 2.6Hz), 4.02 (1H, dd, 10.9 Hz, 2.3 Hz), 3.86 (1H, td, 12.6 Hz, 2.6 Hz),3.60 (1H, 1/2 AB), 3.16 (1H, d, 12.6 Hz), 3.08-2.90 (3H, m), 2.58 (1H,m); ¹⁹F NMR (CD₃OD) −128.4; LCMS: (12 min method) m/z 318.1[M−HCl+H]⁺@Rt 3.954 min.

EXAMPLE 18B2-(2-Fluoro-6-chloro-phenyl)-1-morpholin-2-yl-1-phenyl-ethanolhydrochloride a)1-(4-Benzyl-morpholin-2-yl)-2-(2-chloro-6-fluoro-phenyl)-1-phenyl-ethanol

To a stirred solution of 2-chloro-6-fluorobenzyl magnesium chloride(12.8 mL, 3.20 mmol, 3 equiv., available from Rieke Metals) in anhydroustetrahydrofuran (15 ml) at 0° C. under nitrogen was added a solution of(4-Benzyl-morpholin-2-yl)-phenyl-methanone (300 mg, 1.07 mmol, 1 equiv.)in tetrahydrofuran (5 ml) dropwise over 15 minutes. The reaction wasthen stirred at 0° C. for one hour. The reaction mixture was allowed towarm to room temperature over two hours and stirred for a further 18 h.The solvent was then evaporated “in vacuo” and the residue redissolvedin dichloromethane (30 mL). The organic solution was washed with aqueoussaturated solution of NaHCO₃ (50 mL). The aqueous solution was extractedwith dichloromethane using a hydrophobic phase separator. Thedichloromethane was evaporated “in vacuo” and redissolved in methanol (2mL). The sample was bound to SCX-2 (5 g) and washed with methanol (30mL). The sample was eluted using 2M ammonia in methanol (30 mL). Thesolvent was then evaporated using a reacti-therm blow down station togive 450 mg of a yellow amorphous solid. This material was used in stepb) without further purification. LCMS (6 minutes method) [M+H]⁺=426@Rt3.27 min. major peak.

b) 2-(2-Fluoro-6-chloro-phenyl)-1-morpholin-2-yl-1-phenyl-ethanolhydrochloride

To a solution of1-(4-Benzyl-morpholin-2-yl)-2-(2-chloro-6-fluoro-phenyl)-1-phenyl-ethanol(450 mg, 1 equiv.) in ethyl acetate (15 mL) at room temperature undernitrogen atmosphere was added ammonium formate (1.69 g, 25 equiv.)followed by addition of palladium on charcoal (10%, 450 g.). Thereaction mixture was heated to reflux for 1.5 hours, cooled to roomtemperature and then filtered through Celite. All volatiles wereevaporated under vacuum, and the resulting solid was purified viapreparative HPLC. The isolated white solid was taken up in ethanol.Hydrogen chloride was added (large excess of 2M solution in diethylether) and the mixture was stirred until it became a clear solution.Then all the volatiles were evaporated “in vacuo”, to give 147 mg of thetitle compound as white solid. ¹H NMR (300 MHz, CD₃OD D4) δ: 2.51-2.61(d, 1H), 2.79-2.91 (t, 1H), 2.96-3.09 (m, 1H), 3.09-3.16 (m, 1H),3.32-3.54 (q, 2H), 3.82-3.97 (t, 1H), 4.09-4.24 (t, 2H), 6.73-6.84 (t,1H), 6.93-7.08 (m, 2H), 7.08-7.21 (m, 5H). LCMS (12 minutes method)[M+H]⁺=336@Rt 4.44 min. single major peak.

EXAMPLE 19B 2-(2,5-Dimethoxy-phenyl)-1-morpholin-2-yl-1-phenyl-ethanolhydrochloride a)1-(4-Benzyl-morpholin-2-yl)-2-(2,5-dimethoxy-phenyl)-1-phenyl-ethanol

The procedure for the synthesis of example 18Ba,1-(4-Benzyl-morpholin-2-yl)-2-(2-chloro-6-fluoro-phenyl)-1-phenyl-ethanol, using 2,5-dimethoxybenzyl magnesium chlorideas starting material (available from Rieke Metals) was followed makingnon-critical variations, to yield the title compound. This material wasused in step b) without further purification. LCMS (6 minutes method)[M+H]⁺=434@Rt 3.10 min. major peak.

b) 2-(2,5-Dimethoxy-phenyl)-1-morpholin-2-yl-1-phenyl-ethanolhydrochloride

The procedure for the synthesis of example 18Bb,2-(2-Fluoro-6-chloro-phenyl)-1-morpholin-2-yl-1-phenyl-ethanolhydrochloride, was followed making non-critical variations, to yield thetitle compound.¹H NMR (300 MHz, CD₃OD D4) δ: 2.53-2.62 (d, 1H),2.86-3.10 (m, 3H), 3.13-3.27 (m, 2H), 3.36-3.51 (m, 6H), 3.81-3.93 (t,1H), 4.02-4.08 (d, 1H), 4.15-4.25 (d, 1H), 6.28-6.33 (s, 1H), 6.49-6.64(m, 2H), 7.06-7.22 (m, 5H). LCMS (12 minutes method) [M+H]⁺=344@Rt 4.15min. single major peak.

EXAMPLE 20B 2-(2,4-Difluoro-phenyl)-1-morpholin-2-yl-1-phenyl-ethanolhydrochloride a)1-(4-Benzyl-morpholin-2-yl)-2-(2,4-difluoro-phenyl)-1-phenyl-ethanol

The procedure for the synthesis of example 18Ba,1-(4-Benzyl-morpholin-2-yl)-2-(2-chloro-6-fluoro-phenyl)-1-phenyl-ethanol,using 2,4-difluorobenzyl magnesium bromide as starting material(available from Rieke Metals) was followed making non-criticalvariations, to yield the title compound. This material was used in stepb) without further purification. LCMS (6 minutes method) [M+H]⁺=410@Rt3.19 min. major peak.

b) 2-(2,4-Difluoro-phenyl)-1-morpholin-2-yl-1-phenyl-ethanolhydrochloride

The procedure for the synthesis of example 18Bb,2-(2-Fluoro-6-chloro-phenyl)-1-morpholin-2-yl-1-phenyl-ethanolhydrochloride, was followed making non-critical variations to yield thetitle compound. ¹H NMR (300 MHz, CD₃OD D4) δ: 2.48-2.59 (d, 1H),2.87-3.09 (m, 2H), 3.11-3.17 (m, 2H), 3.26-3.38 (m, 1H), 3.81-3.95 (t,1H), 4.02-4.11 (d, 1H), 4.13-4.25 (d, 1H), 6.48-6.60 (m, 2H), 7.70-6.98(m, 1H) 7.08-7.28 (m, 5H). LCMS (12 minutes method) [M+H]⁺=320@Rt 4.20min. major peak.

EXAMPLE 21B Preparation of2-(2,6-Dichloro-phenyl)-1-morpholin-2-yl-1-phenyl-ethanol hydrochloridea) 1-(4-Benzyl-morpholin-2-yl)-2-(2,6-dichloro-phenyl)-1-phenyl-ethanol

The procedure for the synthesis of example 18Ba,1-(4-Benzyl-morpholin-2-yl)-2-(2-chloro-6-fluoro-phenyl)-1-phenyl-ethanol,using 2,6-dichlorobenzyl magnesium chloride as starting material(available from Rieke Metals) was followed making non-criticalvariations, to yield the title compound. This material was used in stepb) without further purification. LCMS (6 minutes method) [M+H]⁺=442@Rt3.49 min. major peak.

b) 2-(2,6-Dichloro-phenyl)-1-morpholin-2-yl-1-phenyl-ethanolhydrochloride

To a solution of1-(4-Benzyl-morpholin-2-yl)-2-(2,6-dichloro-phenyl)-1-phenyl-ethanol(450 mg, 1 equiv.) in ethyl acetate (15 mL) at room temperature undernitrogen atmosphere was added ammonium formate (1.69 g, 25 equiv.)followed by addition of palladium on charcoal (10%, 45mg.). The reactionmixture was heated to reflux for 3 hour, cooled to room temperature andthen filtered through Celite. All volatiles were evaporated undervacuum, and the resulting solid was purified via preparative HPLC. Theisolated white solid was taken up in ethanol. Hydrogen chloride wasadded (large excess of 2M solution in diethyl ether) and the mixture wasstirred until it became a clear solution. Then all the volatiles wereevaporated “in vacuo”, to give 60 mg of the title compound as whitesolid.¹H NMR (300 MHz, CD₃OD D4) δ: 2.52-2.61 (d, 1H), 2.79-2.96 (t,1H), 2.98-3.13 (t, 1H), 3.15-3.19 (s, 1H), 3.56-3.71 (q, 2H), 3.88-4.02(t, 1H), 4.10-4.21 (d, 1H), 4.29-4.39 (d, 1H), 6.97-7.08 (m, 1H),7.10-7.21 (m, 7H). LCMS (12 minutes method) [M+H]⁺=352@Rt 4.63 min.single major peak.

EXAMPLE 22B Preparation of2-(2,5-Dichloro-phenyl)-1-morpholin-2-yl-1-phenyl-ethanol hydrochloridea) 1-(4-Benzyl-morpholin-2-yl)-2-(2,5-dichloro -phenyl)-1-phenyl-ethanol

The procedure for the synthesis of example 18Ba,1-(4-Benzyl-morpholin-2-yl)-2-(2-chloro-6-fluoro-phenyl)-1-phenyl-ethanol,using 2,5-dichlorobenzyl magnesium chloride as starting material(available from Rieke Metals) was followed making non-criticalvariations, to yield the title compound. This material was used in stepb) without further purification. LCMS (6 minutes method) [M+H]⁺=442@Rt3.48 min. major peak.

b) 2-(2,5-Dichloro-phenyl)-1-morpholin-2-yl-1-phenyl-ethanolhydrochloride

The procedure for the synthesis of example 21Bb,1-(4-Benzyl-morpholin-2-yl)-2-(2,6-dichloro-phenyl)-1-phenyl-ethanol,was followed making non-critical variations to the title compound. ¹HNMR (300 MHz, CD₃OD D4) δ: 2.49-2.61 (d, 1H), 2.88-3.11(m, 2H),3.12-3.24 (m, 1H), 3.24-3.35 (m, 1H), 3.41-3.53 (d, 1H), 3.82-3.96 (m,1H), 4.04-4.25 (m, 2H), 6.90-7.00 (m, 1H), 7.02-7.29 (m, 7H). LCMS (12minutes method) [M+H]⁺=352(Rt 4.86 min. major peak

EXAMPLE 23B Preparation of2-(2,5-Difluoro-phenyl)-1-morpholin-2-yl-1-phenyl-ethanol hydrochloridea) 1-(4-Benzyl-morpholin-2-yl)-2-(2,5-difluoro -phenyl)-1-phenyl-ethanol

The procedure for the synthesis of example 18Ba,1-(4-Benzyl-morpholin-2-yl)-2-(2-chloro-6-fluoro-phenyl)-1-phenyl-ethanol, using 2,5-difluorobenzyl magnesium bromide asstarting material (available from Rieke Metals) was followed makingnon-critical variations, to yield the title compound. This material wasused in step b) without further purification. LCMS (6 minutes method)[M+H]⁺=410@Rt 3.11 min. major peak.

b) 2-(2,5-Difluoro-phenyl)-1-morpholin-2-yl-1-phenyl-ethanolhydrochloride

The procedure for the synthesis of example 18Bb,2-(2-Fluoro-6-chloro-phenyl)-1-morpholin-2-yl-1-phenyl-ethanolhydrochloride, was followed making non-critical variations, to yield thetitle compound. H NMR (300 MHz, CD₃OD D4) δ: 2.48-2.59 (d, 1H),2.87-3.09 (m, 2H), 3.11-3.17 (m, 1H), 3.26-3.38 (m, 2H), 3.81-3.95 (t,1H), 4.02-4.11 (d, 1H), 4.13-4.25 (d, 1H), 6.62-6.77 (m, 3H), 7.08-7.28(m, 5H). LCMS (12 minutes method) [M+H]⁺=320@Rt 4.20 min. single majorpeak.

EXAMPLE 24B Preparation of2-(2-Fluoro-5-phenyl-phenyl)-1-morpholin-2-yl-1-phenyl-ethanolhydrochloride a)1-(4-Benzyl-morpholin-2-yl)-2-(-2-biphenyl-5-flouro-phenyl)-1-phenyl-ethanol

The procedure for the synthesis of example 18Ba,1-(4-Benzyl-morpholin-2-yl)-2-(2-chloro-6-fluoro-phenyl)-1-phenyl-ethanol, using 2-phenyl-5-fluorobenzyl magnesiumbromide as starting material was followed making non-criticalvariations, to yield the title compound. This material was used in stepb) without further purification. LCMS (6 minutes method) [M+H]⁺=468@Rt3.62 min. major peak.

b) 2-(2-Fluoro-5-phenyl-phenyl)-1-morpholin-2-yl-1-phenyl-ethanolhydrochloride

The procedure for the synthesis of example 18Bb,2-(2-Fluoro-6-chloro-phenyl)-1-morpholin-2-yl-1-phenyl-ethanolhydrochloride, was followed making non-critical variations to the titlecompound. ¹H NMR (300 MHz, CD₃OD D4) δ: 2.35-2.48 (d, 1H), 2.77-2.91 (t,1H), 2.91-3.04 (m, 1H), 3.04-3.16 (m, 1H), 3.22-3.28 (m, 1H), 3.30-3.42(m, 1H), 3.66-3.87 (m, 2H), 4.01-4.14 (d, 1H), 6.70-6.89 (m, 5H),6.98-7.11 (m, 4H), 7.14-7.25 (m, 4H). LCMS (12 minutes method)[M+H]⁺=378@Rt 5.22 min. major peak.

Solid Phase Synthesis of Compounds of Formulae (IB)

Compounds of the invention wherein Ar₁ is substituted with an aromaticgroup (i.e., pyridyl, thiophenyl, and optionally substituted phenyl) canbe prepared by solid phase synthesis using the route shown below (theblack dot represents polystyrene resin).

The sequence is preferably performed on a polystyrene resin, withoutcharacterization of the resin-bound intermediates.

-   -   i) Aliquots (52 mg, 0.05 mmoles) of p-nitrophenyl carbonate        resin (Novabiochem) were dispensed into 4.5 ml MiniBlock        reaction tubes (Mettler-Toledo). To each resin was added DMF        (0.5 ml) followed by a 0.2M solution of        2-(2-bromo-phenyl)-1-morpholin-2-yl-1-phenyl-ethanol in DMF (0.5        ml, 0.1 mmoles). The tubes were sealed and agitated by orbital        shaking for 24 hrs. The resins were then filtered and washed        with DMF (3×1.0 ml), a solution of diisopropylethylamine        (0.25 ml) in DMF (1.0 ml) and finally DMF (4×1.0 ml).    -   ii) To each resin was added a 2M solution of an optionally        substituted aryl boronic acid in DMF (0.5 ml, 1.0 mmoles), a        0.5M solution of triphenylphosphine in DMF (0.2 ml, 0.1 mmoles),        a 0.25M solution of Pd(II) acetate in DMF (0.2 ml, 0.05 mmoles)        and a 1.25M solution of caesium carbonate in water (0.1 ml,        0.125 mmoles). The tubes were sealed, agitated by orbital        shaking and heated at 80° for 20 hrs. The reactions were then        cooled to ambient temperature and the resins washed with DMF        (2×1.0 ml), MeOH (3×1.0 ml) and DCM (4×1.0 ml).    -   iii) To each resin was added a TFA/H₂O mixture (95:5 v/v, 1 ml).        The tubes were sealed and agitated by orbital shaking for 6 hrs.        The reactions were filtered and washed with DCM (2×2 ml).        Appropriate filtrates and washings were combined and volatile        components removed by vacuum evaporation. Each residue was        dissolved in MeOH (1 ml) and the solutions applied to        MeOH-washed SCX-2 cartridges (0.5 g/3.0 ml) (Jones        Chromatography). After draining under gravity the cartridges        were washed with MeOH (2.5 ml) and the products then eluted        using a 2M solution of ammonia in MeOH (2.5 ml). Removal of        volatile components by vacuum evaporation gave the desired        products which were purified by preparative LCMS.

By this means were prepared:

EXAMPLE 25B2-(4′-methyl-biphenyl-2-yl)-1-morpholin-2-yl-1-phenyl-ethanol, RT (6 mingradient) 3.11 min, [M+H]⁺ 374.2 EXAMPLE 26B2-(4′-chloro-biphenyl-2-yl)-1-morpholin-2-yl-l -phenyl-ethanol, RT (6min gradient) 3.36 min, [M+H]⁺ 394.2 EXAMPLE 27B2-(4′-methoxy-biphenyl-2-yl)-1-morpholin-2-yl-1-phenyl-ethanol, RT (6min gradient) 3.37 min, [M+H]⁺ 390.2 EXAMPLE 28B2-(3′-fluoro-biphenyl-2-yl)-1-morpholin-2-yl-1-phenyl-ethanol, RT (6 mingradient) 3.39 min, [M+H]⁺ 378.4 EXAMPLE 29B2-(3′-chloro-biphenyl-2-yl)-1-morpholin-2-yl-1-phenyl-ethanol, RT (6 mingradient) 3.53 min, [M+H]⁺ 394.4 EXAMPLE 30B2-(3′-methoxy-biphenyl-2-yl)-1-morpholin-2-yl-1-phenyl-ethanol, RT (6min gradient) 3.31 min, [M+H]⁺ 390.4 EXAMPLE 31B2-(3′-methyl-biphenyl-2-yl)-1-morpholin-2-yl-1-phenyl-ethanol, RT (6 mingradient) 3.45 min, [M+H]⁺ 374.4 EXAMPLE 32B2-(3′,5′-dichloro-biphenyl-2-yl)-1-morpholin-2-yl-1-phenyl-ethanol, RT(6 min gradient) 3.71 min, [M+H]⁺ 428.3 EXAMPLE 33B2-(2′,4′-dimethyl-biphenyl-2-yl)-1-morpholin-2-yl-1-phenyl-ethanol, RT(6 min gradient) 3.59 min, [M+H]⁺ 388.4 EXAMPLE 34B2-(2′,4′-dimethoxy-biphenyl-2-yl)-1-morpholin-2-yl-1-phenyl-ethanol, RT(6 min gradient) 3.33 min, [M+H]⁺ 420.4 EXAMPLE 35B1-morpholin-2-yl-1-phenyl-2-(2-pyridin-3-yl-phenyl)-ethanol, RT (6 mingradient) 2.17 min, [M+H]⁺ 361.4 EXAMPLE 36B1-morpholin-2-yl-1-phenyl-2-(2-thiophen-3-yl-phenyl)-ethanol, 3.25 min,[M+H]⁺ 366.4 EXAMPLE 37B2-(3′,4′-dichloro-biphenyl-2-yl)-1-morpholin-2-yl-1-phenyl-ethanol, RT(6 min gradient) 3.56 min, [M+H]⁺ 428.1

The following examples illustrate compounds of of Formulae (IC) aboveand methods for their preparation.

General Synthetic Procedures for the Preparation of Examples IC-17C

The numbers included in the following Sections refer to the compoundsillustrated in Schemes 2C to 6C herein.

General Procedure 1C: Preparation of Racemic N-Substituted Aryl Thiols

To a solution of 5Ca,5Cb (0.02 g, 0.52 mmol) and the requisite arylthiol (1.1 eq) in anhydrous dimethylformamide (1 ml) at room temperatureunder nitrogen was added cesium carbonate (1.1 eq, 0.19 g, 0.57 mmol).The reaction mixture was heated to 95° C. for 2 hours. The reactionmixture was allowed to cool to room temperature, diluted with ethylacetate, then washed sequentially with water, brine, dried overmagnesium sulphate and finally concentrated in vacuo.

General Procedure 2Ca: Deprotection of N-Substituted Aryl Thiols

To a solution of the requisite N-benzyl aryl thiol in anhydrousdichloromethane (5 ml) was added solid supported Hünig's base (Argonaut,3.56 mmol/g, 2 eq) and a-chloroethyl chloroformate (3 to 1 0 eq) at roomtemperature under nitrogen. The reaction mixture was heated to 40° C.and followed by LCMS analysis. After completion the reaction mixture wasfiltered, and the resin washed with dichloromethane. The combinedorganic phases were concentrated in vacuo. Methanol (HPLC grade, 25 ml)was added and the solution heated to 60° C. for 1.5 to 4 hours. Aftercomplete consumption of starting material the methanol solution wasevaporated to give a solid which was further purified as detailed forindividual compounds.

General Procedure 2Cb: Deprotection of N-Substituted Aryl Thiols

To a solution of the requisite N-benzyl aryl thiol (1 eq) in ethylacetate at room temperature was added phenylchloroformate (3 eq). Themixture was warmed under reflux for 2 hours. The mixture was then cooledto room temperature and 30% NaOH with water was added over 1 hour. Thebiphasic system was stirred for 1.5 hours at room temperature and theorganic layer was separated. The organic layer was washed with water,dried over MgSO₄, filtered and rinsed with ethyl acetate.

To the mixture of carbamate and benzylchloride in ethyl acetate wasadded 5.6M dimethylamine in ethanol. The solution was warmed underreflux (70-72° C.) for 2 hours. After cooling at room temperature, waterand 12N HCl were added and the mixture was stirred for 10 minutes. Thelayers were separated and the organic phase was washed twice with water.Then the organic layer was concentrated (T=50° C.) untilcrystallization. MeOH was added and approx. 40% of solvent was thenremoved under reduce pressure, this operation was repeated. Theheterogeneous mixture was stirred for 0.5 hours at room temperature andfiltered. The precipitate was washed twice with MeOH and dried underreduce pressure at 40° C. to yield the carbamate.

To a biphasic mixture of 30% NaOH and isopropanol warmed to 65° C., wasadded the carbamate. The heterogeneous mixture was warmed under refluxfor 4 hours and then cooled to room temperature and post-agitatedovernight. The organic layer was concentrated under reduce pressure andthe yellow solid obtained was added to a mixture of AcOEt and 1N NaOH.After separation of the layers, the organic one was washed with 1N NaOH.The aqueous layers were combined and extracted with AcOEt. The combinedorganic layers were dried over MgSO₄, filtered and concentrated underreduce pressure to dryness to obtain the free amine.

General Procedure 3C: Conversion of Amines Into Hydrochloride Salts

To a solution of the requisite amine in dry diethyl ether (1 ml) wasadded hydrochloric acid (500 μl of a 1M solution in diethyl ether). Awhite precipitate immediately formed. The suspension was then sonicatedfor 5 minutes. Ether was blown off with a stream of nitrogen and thesamples were dried under high vacuum for several hours to give thehydrochloride salts in near quantitative yield as white solids.

General Procedure 4C: Aldoladdition With Substituted Benzaldehydes

Preparation of 38Ca,38Cb: 39Ca,39Cb: 40Ca,40Cb

N-Benzylmorpholinone (1.0 eq) and the requisite aldehyde (1.1 eq) weredissolved in anhydrous tetrahydrofuran (25 ml) under nitrogen and thereaction cooled to −78° C. Then, lithium diisopropylamide (1.1 eq of a2M solution in heptane/tetrahydrofuran/ethylbenzene) was added overapproximately 20 minutes, whilst maintaining the reaction temperaturebelow −78° C. The resulting yellow solution was stirred at −78° C. for 1hour and then allowed to warm to room temperature. The reaction wasquenched with saturated ammonium chloride solution (25 ml) and extractedinto ethyl acetate. The combined organic layers were dried withmagnesium sulphate, filtered and concentrated in vacuo, to give a yellowoil which was purified by column chromatography on silica gel (eluent:ethyl acetate/hexane 70/100 [v/v]).

General Procedure 5C: Reduction of Substituted Aldol Adducts

Preparation of 41Ca,41Cb: 42Ca,42Cb; 43Ca,43Cb

To a solution of the requisite amide 38Ca,38Cb, 39Ca,39Cb or 40Ca,40Cb(1.1 mmol) in anhydrous tetrahydrofuran under nitrogen at roomtemperature was slowly added borane (4 eq of a 1M solution intetrahydrofuran). The solution was stirred at 60° C. for 2 hours. Thereaction was cooled to room temperature; dry methanol (excess) wasslowly added, followed by aqueous hydrochloric acid solution (1M,excess). The reaction mixture was heated to 60° C. for 1 hour andquenched with aqueous potassium carbonate solution (1M, excess) andextracted with diethyl ether. The combined organic layers were washedwith brine, dried with magnesium sulphate, filtered and concentrated invacuo yielding a yellow oil which was purified by column chromatographyon silica gel (eluent: ethyl acetate/hexane 10/100 [v/v]).

Preparation of Intermediates for the Synthesis of Examples 1C-17C4-Benzylmorpholin-3-one (2C)

A solution of N-benzyl-N-(2-hydroxyethyl) chloroacetamide (627.7 g, 2.76mol) in tert-butanol (0.9 l) was stirred under nitrogen while warming to25-30° C. Potassium tert-butoxide (2.897 l of a 1M solution intert-butanol, 2.90 mol, 1.05 eq) was added over 2 hours. The reactionmixture was then stirred at room temperature for 90 minutes. Ice-coldwater (6 l) was added and the resultant cloudy solution extracted withethyl acetate. The combined organic layers were washed with brine, driedover magnesium sulphate and evaporated in vacuo to give a light brownoil (441 g, 84%), which was used in the next stage without furtherpurification; MW 191.23; C₁₁H₁₃NO₂; ¹H NMR (CDCl₃): 7.29-7.40 (5H, m),4.67 (2H, s), 4.28 (2H, s), 3.87 (2H, t, 5 Hz), 3.31 (2H, t, 5 Hz);LCMS: (12 min method) m/z 192 [M+H]+@Rt 1.00 min.

(2S)-(4-Benzyl-morpholin-2-yl)-phenyl-methanone (3Ca) and(2R)-(4-Benzyl-morpholin-2-yl)-phenyl-methanone (3Cb)

Described above under the “Synthesis of Intermediates” section forcompounds of Formula (IB).

(S)-Phenyl[(2S)-4-(phenylmethyl)morpholin-2-yl]methanol (4Ca)

To a stirred solution of [(−)-B-chlorodisopinocampheylborane] (45 g, 140mmol) in dry tetrahydrofuran (300 ml) under nitrogen was added 3Ca (7.97g, 28.4 mmol) in one portion. The reaction mixture was stirred at roomtemperature for 18 hours. The mixture was evaporated in vacuo andextracted from 2M aqueous sodium hydroxide solution into ethyl acetate.The combined organic extracts were washed with brine, dried, filteredand evaporated. The crude product was taken up in chloroform/methanol(1:1 [v/v]) and absorbed onto 150 g SCX-2 ion exchange resin. Afterelution of borane residues with methanol the product was eluted with 2Mammonia in methanol. Removal of solvent in vacuo yielded the product asyellow oil. This was further purified by flash chromatography (eluent:ethyl acetate/isobexane 80/20 [v/v]). After removal of solvents, theproduct crystallised on standing (6.73 g, 84%); MW 283.37; C₁₈H₂₁NO₂; ¹HNMR (CDCl₃): 7.32-7.45 (10H, m), 4.67 (1H, d, 7 Hz), 4.03 (1H, dt, 11 Hzand 2 Hz), 3.86-3.73 (2H, m), 3.64 (1H, d, 13 Hz), 3.39 (1H, d, 13 Hz),3.30 (1H, br, s), 2.68 (1H, d, 12 Hz), 2.56 (1H, d, 10 Hz), 2.28-2.15(2H, m); LCMS: m/z 284 [M+H]+@Rt 0.95 min.

(2S)-2-[(R)-bromo(phenyl)methyl]-4-(phenylmethyl)morpholine (5Ca)

To a solution of 4Ca (4.71 g, 16.6 mmol) in anhydrous chloroform (200ml) under nitrogen was added triphenylphosphine dibromide (14.04 g,33.26 mmol). The reaction mixture was heated at 60° C. overnight. Themixture was allowed to cool to room temperature then washed withsaturated aqueous sodium carbonate solution, dried over sodium sulphateand concentrated in vacuo. The resulting residue was purified by flashchromatography on silica (eluent: ethyl acetate/isohexane gradient 10/90to 30/70 [v/v]) to give 5Ca as a white solid (4.63 g, 81%); MW 346.27;C₁₈H₂₀BrNO; ¹H NMR (CDCl₃): 7.14-7.39 (10H, m), 4.83 (1H, d, 7 Hz), 4.01(1H, br, t, 8 Hz), 3.73 (1H, br, d, 11 Hz), 3.60-3.48 (2H, m), 3.39 (1H,d, 12 Hz), 3.20 (1H, d, 11 Hz), 2.50 (1H, d, 10 Hz), 2.07 (2H, t, 10Hz); LCMS: (6 min method) m/z 346 [M]+@Rt 2.51 min.

(2S)-2-[(S)-Hydroxy(phenyl)methyl]-4-(phenylmethyl)morpholin-3-one (6Ca)and (2S)-2-1(R)-Hydroxy(phenyl)methyl]-4-(phenylmethyl)morpholin-3-one(6Cb) and(2R)-2-[(S)-Hydroxy(phenyl)methyl]-4-(phenylmethyl)morpholin-3-one (6Cc)and (2R)-2-[(R)-Hydroxy(phenyl)methyl]-4-(phenylmethyl)morpholin-3-one(6Cd)

To a stirred solution of 2C (5.02 g, 26 mmol) in anhydroustetrahydrofuran (25 ml) under nitrogen at −78° C. was added lithiumdiisopropylamide (1.5 eq, 39 mmol, 19.5 ml of a 2M solution inheptane/tetrahydrofuran/ethylbenzene) over approximately 20 minutes,whilst maintaining the reaction temperature below −75° C. The resultingbrown solution was stirred for a further 30 minutes at −78° C., beforebeing added over approximately 30 minutes to a solution of benzaldehyde(1.2 eq, 3.29 g, 31 mmol) in anhydrous tetrahydrofuran (15 ml) undernitrogen at −78° C., whilst again maintaining the reaction temperaturebelow −75° C. The resulting yellow solution was stirred at −78° C. for 1hour, before being allowed to warm to room temperature slowly over 1hour. The reaction mixture was cautiously quenched by addition ofsaturated ammonium chloride solution (50 ml) and the tetrahydrofuran wasevaporated in vacuo. The resulting cloudy aqueous solution was extractedwith dichloromethane, and the organic extracts were combined, washedwith brine, dried over sodium sulphate and the dichloromethaneevaporated in vacuo to give a thick brown oil (9.2 g), which partiallycrystallised on standing. After purification by flash columnchromatography (eluent: ethyl acetate/dichloromethane 10/90 to 20/80gradient [v/v]) 6Ca,6Cb was obtained as light red crystals (2.46 g,32%); MW 297.36; C₁₈H₁₉NO₃; ¹H NMR (CDCl₃): 7.36-7.41 (2H, m), 7.16-7.31(6H, m), 6.86-6.91 (2H, m), 5.14 (1H, d, J 3 Hz), 4.71 (1H ,d, 14 Hz),4.48 (1H, d, J 3 Hz), 4.25 (1H, d, 14 Hz), 4.20 (1H, br, s), 3.89 (1H,ddd, 12 Hz, 3 Hz, 2 Hz), 3.67 (1H, dt, 11 Hz, 3 Hz), 3.16 (1H, dt, 12 Hzand 4 Hz), 2.86 (1H, br, d, 12 Hz); LCMS: m/z 298 [M+H]+@Rt 1.24 min.6Cc, 6Cd was isolated as a brown solid (1.42 g) contaminated with 2C.Trituration with ethyl acetate afforded pure 6Cc,6Cd as a white solid(0.484 g, 6%); MW 297.36; C₁₈H₁₉NO₃; ¹H NMR (CDCl₃): 7.55-7.61 (2H, m),7.36-7.50 (6H, m), 7.25-7.31 (2H, m), 5.21 (1H, d, 2 Hz), 5.09 (1H, d, J7 Hz and 2 Hz), 4.73 (2H, s), 4.37 (1H, d, J 8 Hz), 4.01 (1H, ddd, 12Hz, 3 Hz, 2 Hz), 3.77 (1H, dt, 11 Hz, 4 Hz), 3.50 (1H, dt, 12 Hz, 4 Hz),3.16 (1H, br, d, 12 Hz); LCMS: m/z 298 [M+H]+@Rt 1.24 min.

(S)-Phenyl[(2S)-4-(phenylmethyl)morpholin-2-yl]methanol (4Ca) and(R)-Phenyl[(2R)-4-(phenylmethyl)morpholin-2-yl]methanol (4Cb)

To a solution of 6Ca,6Cb (0.033 g, 1.1 mmol) in anhydrous THF (5 ml)under nitrogen at room temperature was slowly added borane (4 eq, 4.4 mlof a 1 M solution in tetrahydrofuran, 4.4 mmol). The solution wasstirred at 60° C. for 2 hours. After cooling down to room temperature,dry methanol (2 ml) was slowly added to quench excess borane reagent.After addition of aqueous hydrochloric acid solution (2 ml of a 1Msolution) the reaction mixture was heated to 60° C. for 1 hour. Theorganic solvents were evaporated in vacuo and the concentrated solutionwas poured onto aqueous potassium carbonate solution (10 ml of a 1Msolution) and extracted with diethyl ether (2×20 ml). The combinedorganic layers were washed with brine, water, dried over magnesiumsulphate and concentrated in vacuo. Purification by flash columnchromatography (eluent: hexane/ethyl acetate/triethylamine 90/9/1[v/v/v]) gave a viscous oil (0.19 g, 60%); MW 283.37; C₁₈H₂₁NO₂; ¹H NMR(CDCl3): 7.45-7.32 (10H, m), 4.67 (1H, d, 7 Hz), 4.03 (1H, dt, 11 Hz,2.7 Hz), 3.86-3.73 (2H, m), 3.64 (1H, d, 13 Hz), 3.39 (1H, d, 13 Hz),3.30 (1H, br, s), 2.68 (1H, d, 13 Hz), 2.56 (1H, d, 11 Hz), 2.28-2.15(2H, m); LCMS: m/z 284 [M+H]+@Rt 0.95 min.

(R)-[(2S)4-Benzylmorpholinyl](phenyl)methanol (4Cc) and(S)-[(2R)-4-Benzylmorpholinyl](phenyl)methanol (4Cd)

Using the procedure described for the preparation of 4Ca,4Cb startingfrom 6Cc,6Cd (0.14 g, 0.45 mmol) 4Cc,4Cd was obtained as a viscous oil(0.098 g, 68%); MW 283.37; C₁₈H₂₁NO₂; ¹H NMR (CDCl₃): 7.17-7.28 (10H,m), 4.80 (1H, d, 4 Hz), 3.88 (1H, dt, 11 Hz, 3 Hz), 3.72 (1H, m),3.61-3.68 (1H, m), 3.50 (1H, d, 13 Hz), 3.25 (1H, d, 13 Hz), 2.52 (2H,br, t, 12 Hz), 2.17 (1H, t, 11 Hz), 2.08 (1H, td, 11 Hz, 3 Hz); LCMS:m/z 284 [M+H]+@Rt 0.98 min.

(2S)-2-[(R)-Bromo(phenyl)methyl]-4-(phenylmethyl)morpholine (5Ca) and(2R)-2-[(S)-Bromo(phenyl)methyl]-4-(phenylmethyl)morpholine (5Cb)

To a solution of 4Ca,4Cb (10.27 g, 36.29 mmol) in anhydrousdichloromethane (150 ml) under nitrogen at room temperature was addedfreshly recrystallised triphenylphosphine (13.32 g, 50.80 mmol, 1.4 eq)followed by carbon tetrabromide (16.85 g, 50.8 mmol, 1.4 eq) as asolution in anhydrous dichloromethane (50 ml). After 15 minutes thereaction mixture was diluted with dichloromethane (100 ml) and washedwith saturated aqueous solution of sodium hydrogencarbonate, brine,dried over magnesium sulphate and concentrated in vacuo to give anorange oil (42.0 g). To the orange oil was added diethyl ether (200 ml)and the resulting suspension was sonicated for 30 minutes. The solventwas decanted and the process repeated with a further portion of diethylether. The combined organic extracts were concentrated in vacuo to yieldan orange solid (22.0 g) which was purified by flash columnchromatography (eluent: ethyl acetate/hexane/triethylamine 10/89.5/0.5[v/v/v]) 5Ca,5Cb was otained as a white solid (7.20 g, 57%). AlternativeWork-up: The reaction mixture was poured onto a silica (160 g)filtration pad which was washed with dichloromethane (14×250 ml). Afterremoval of solvents in vacuo and purification by flash columnchromatography (eluent: ethyl acetate/hexane/triethylamine gradient5/94.5/0.5 to 10/89.5/0.5 [v/v/v]) to give a white solid (6.05 g, 48%);MW 346.27; C₁₈H₂₀BrNO; ¹H NMR (CDCl₃): 7.14-7.39 (10H, m), 4.83 (1H, d,7 Hz), 4.01 (1H, br, t, 8 Hz), 3.73 (1H, br, d, 11 Hz), 3.48-3.60 (2H,m), 3.39 (1H, d, 12 Hz), 3.20 (1H, d, 11 Hz), 2.50 (1H, d, 10 Hz), 2.07(2H, t, 11 Hz); LCMS: m/z 348/346 [M+H]+@Rt 1.20 min.

4-[(1R)-1-Phenylethyl]morpholine-(2S)-carbonitrile (47Ca) and4-[(1R)-1-Phenylethyl]morpholine-(2R)-carbonitrile (47Cb)

To (R)-(−)-2-hydroxyethyl-a-phenethylamine (1.65 g, 10.0 mmol) indiethyl ether (10 ml) was added at room temperature2-chloroacrylonitrile (0.80 ml, 10.0 mmol) with stirring. The mixturewas stirred at room temperature for 4.5 days when additional2-chloroacrylonitrile (0.8 ml, 10.0 mmol) was added. After stirringanother 3.5 days, the reaction mixture was concentrated in vacuo to givean oil. The oil was dissolved in dry tetrahydrofuran (30 ml), cooledunder nitrogen to 0° C. and potassium tert-butoxide (1.23 g, 11.0 mmol)added. The solution was stirred at 0° C. for 2 hours then at reflux for1.5 hours, cooled, diluted with diethyl ether and washed with aqueoussaturated sodium bicarbonate. The organic phase was extracted with 2Nhydrochloric acid and the aqueous made basic by addition of solid sodiumbicarbonate and extracted with diethyl ether. The organic phase wasdried over magnesium sulphate, filtered and evaporated to a brown oil.The crude product was purified by flash chromatography (eluent: ethylacetate/hexane gradient 100% ethyl acetate to 50/50 [v/v]) to give47Ca,47Cb as a colourless oil (0.58 g, 27%%); MW 216.29; C₁₃H₁₆N₂O; ¹HNMR (CDCl₃) 7.25-7.38 (5H, m), 4.6 (1H, dd), 4.54 (1H, dd), 3.91-4.06(2H, m), 3.66-3.82 (2H, m), 3.39-3.49 (2H, m), 2.30-2. 89 (4H, m), 1.39(3H, d). m/z [M+H]⁺ 217.

Phenyl{(2S)-4-[(1R)-1-phenylethyl]morpholin-2-yl}methanone (48Ca) andPhenyl{(2R)-4-[(1R)-1-phenylethyl]morpholin-2-yl}methanone (48Cb)

To a stirred solution of 47Ca,47Cb (0.57 g, 2.64 mmol) in drytetrahydrofurane (10 ml) at 0° C. under nitrogen was added a solution ofphenylmagnesium chloride in tetrahydrofurane (2.0 M, 2.67 ml) dropwiseover 2 minutes. The pale yellow solution was stirred at 0° C. for 30minutes and then allowed to warm to room temperature. After 2 hours themixture was cooled, quenched with 2M hydrochloric acid and was stirredvigorously for 1 hour at room temperature. After addition of water andextraction with ethyl acetate, the combined organic layers were washedwith brine, dried over magnesium sulphate, filtered and evaporated togive an oil (0.63 g). After purification by column chromatography(eluent: ethyl acetate/hexane gradient 0/100 to 20/80 [v/v]) 48Ca wasobtained as an oil (0.15 g, 19%%); MW 295.38; C₁₉H₂₁NO₂; ¹H NMR (CDCl₃)8.00 (2H, d), 7.60 (1H, t), 7.50 (2H, t), 7.20-7.35 (5H, m), 4.96 (1H,d), 3.93-4.00 (1H, m), 3.70-3.80 (1H, m), 3.41 (1H, q), 3.25 (1H, br,d), 2.59 (1H, br, d), 2.13-2. 36 (2H, m), 1.38 (3H, d). m/z [M+H]⁺ 296followed by 48Cb as an oil (0.27 g, 35%%) ¹H NMR (CDCl₃) 7.90 (2H, d),7.54 (1H, t), 7.45 (2H, t), 7.20-7.38 (5H, m), 4.85 (1H, d), 4.05-4.12(1H, m), 3.80-3.92 (1H, m), 3.43 (1H, q), 2.86-3.00 (2H, m), 2.29-2.40(1H, m), 2.21 (1H, t), 1.38 (3H, d). m/z [M+H]⁺ 296.

(R)-Phenyl{(2S)-4-[(1R)-1-phenylethyl]morpholin-2-yl}methanol (50C)

To a stirred solution of 48Ca (0.08 g, 0.26 mmol) and triphenylsilane(0.34 g, 1.31 mmol) in dichloromethane (4 ml) cooled to 0° C. was addedboron trifluoride etherate (0.09 g, 0.66 mmol) followed bytrifluoroacetic acid (0.36 ml, 63 mmol). The reaction mixture wasallowed to warm to room temperature and diluted after three hours withdichloromethane (20 ml) and neutralised with aqueous sodium bicarbonate.The organic phase was dried over magnesium sulphate, filtered andevaporated to give the required product. This was purified as itshydrochloric acid salt crystallising from isopropanol and diethyl ether(0.05 g, 69%%); MW 297.4; C₁₉H₂₃NO₂; ¹H NMR (CDCl₃) on free base7.08-7.29 (10H, m), 4.78 (1H, d), 3.90-4.00 (1H, m), 3.57-3.68 (2H, m),3.33 (1H, q), 2.53-2.64 (1H, m), 2.37-2.47 (1H, m), 2.09-2.26 (2H, m),1.29 (3H, d). m/z [M+H]⁺ 298.

(R)-Phenyl{(2S)-4-[(1R)-1-phenylethyl]morpholin-2-yl}methylmethanesulphonate (51C)

To a solution of 50C (0.05 g, 0.17 mmol) in dichloromethane (1 ml) atroom temperature was added polymer supported Hünig's base ((Argonaut,3.56 mmol/g, 0.089 g, 0.32 mmol, 1.9 eq) and methanesulphonyl chloride(0.02 g, 0.19 mmol). The mixture was stirred under nitrogen for 6 hoursthen filtered and concentrated in vacuo. The crude product was purifiedby flash column chromatography (eluent: ethyl acetate/heptane 33/67[v/v]) to give 51C as a colourless oil (0.035 g, 55%%); MW 375.49;C₂₀H₂₅NO₄S ¹H NMR (CDCl₃) 7.20-7.35 (10H, m), 5.46 (1H, d), 3.79-3.88(2H, m), 3.59 (1H,td), 3.4 (1H, q), 2.68-2.78 (2H, m), 2.68 (3H, s),2.03-2.24 (2H, m), 1.34 (3H, d). m/z [M+H]⁺ 376.

(2S)-4-[(1R)-1-Phenylethyl]-2-((S)-phenyl{[2-(trifluoromethyl)phenyl]thio}methyl)morpholine(52C)

A mixture of 51C (0.035 g, 0.093 mmol), potassium carbonate (0.026 g,0.19 mmol) and 2-trifluoromethylbenzenethiol (0.084 g, 0.47 mmol) indry, degassed dimethylformamide (0.5 ml) was stirred under nitrogen atroom temperature for 3 days. The reaction mixture was diluted with waterand extracted with diethyl ether. The extracts was washed with water andbrine, dried over magnesium sulphate, filtered and evaporated to give acolourless oil (0.03 g, 71%). Purification by flash columnchromatography (eluent: ethyl acetate/heptane 20/80 [v/v]) gave 52C as acolourless oil (0.03 g, 71%); MW 457.56; C₂₆H₂₆F₃NOS ¹H NMR (CDCl₃) 7.53(1H, d), 7.10-7.28 (13H, m), 4.39 (1H, d), 3.85-4.04 (2H, m), 3.8 (1H,td), 3.35 (1H, q), 2.70 (1H, d), 2.40 (1H, d), 2.30 (1H, td), 2.10-2.20(1H, m), 1.29 (3H, d). m/z [M+H]⁺ 458.

EXAMPLE 1C(2S)-2-((S)-Phenyl{[2-(trifluoromethyl)phenyl]thio}methyl)morpholine(9C) (S)-Phenyl[(2S)-4-(phenylmethyl)morpholin-2-yl]methyl2-trifluoromethyl)phenyl sulfide (8C)

Compound 8C was obtained from 5Ca (4.00 g, 11.55 mmol),2-trifluoromethyl thiophenol (2.47 g, 13.86 mmol, 1.2 eq) and caesiumcarbonate (4.95 g, 15.24 mmol, 1.1 eq) in dimethylformamide (60 ml) as abrown oil following a modification of General Procedure 1C in which thereaction was carried out over 1 hour (6.04 g). The oil was purified byflash column chromatography (eluent: hexane/ethyl acetate gradient 100to 90/10 [v/v]) to give a yellow oil (4.83 g, 94%); MW 443.54;C₂₅H₂₄F₃NOS; ¹H NMR (CDCl₃): 7.60 (1H, dd, 7 Hz, 1 Hz), 7.17-7.39 (13H,m), 4.50 (1H, d, 7 Hz), 3.97-4.12 (2H, m), 3.73 (1H, dt, 10 Hz, 2 Hz),3.59 (1H, d, 13 Hz), 3.37 (1H, d, 13 Hz), 2.57-2.68 (2H, m); 2.18-2.38(2H, m); LCMS (2.5 minute method): m/z 445 [M+H]+@Rt 1.50 min.

(2S)-2-((S)-Phenyl{[2-(trifluoromethyl)phenyl]thio}methyl)morpholine(9C)

Compound 9C (Example 1C) was obtained from 8C (5.25 g, 11.84 mmol),solid supported Hünig's base (Argonaut, 3.56 mmol/g, 6.64 g, 23.67 mmol,2 eq) and α-chloroethyl chloroformate (3.83 ml, 35.51 mmol, 3 eq) inanhydrous dichloromethane (75 ml) following General Procedure 2Ca. Afterevaporation of solvents a light brown solid (5.60 g) was obtained whichwas recrystallised from iso-propanol. The solid was suspended in ethylacetate and washed with an aqueous solution of sodium hydroxide (50 mlof a 1M solution). The organic layer was washed with brine, dried overmagnesium sulphate and concentrated in vacuo to yield the free amine asa colourless oil (3.10 g, 74%); MW 353.41; C₁₈H₁₈F₃NOS; ¹H NMR (CDCl₃):7.46 (1H, d, 8 Hz), 7.24 (1H, d, 7 Hz), 7.05-7.2 (7H, m), 4.28 (1H, d, 8Hz), 3.92 (1H, d, 11 Hz), 3.80 (1H, q, 7 Hz), 3.58 (1H, dt, 2 Hz and 11Hz), 2.69-2.87 (2H, m), 2.59 (2H, d, 6 Hz), 2.13-1.90 (1H, br s); LCMS(10 minute method): m/z 354 [M+H]+@Rt 5.26 min. The hydrochloride saltof 9 was obtained following General Procedure 3C.

An alternative method for the preparation of compound 9C (Example 1C),according to Scheme 6C, is as follows:

To a suspension of polymer supported Hünig's base (0.11 g, 0.40 mmol)and 52C (0.03 g, 0.066 mmol) in dry dichloromethane (1 ml) was addedα-chloroethyl chloroformate (0.09 g, 0.066 mmol) at room temperatureunder nitrogen. The mixture was stirred at room temperature over theweekend then filtered and concentrated in vacuo. This was taken up inmethanol, heated at 70° C. for 2 hours, cooled, and purified by SCXchromatography (eluent: ammonia/methanol 1/1 [v/v]) to give 9C as acolourless oil (0.01 g, 43%). The spectroscopic data for 9C obtained bythe route outlined here was identical to the data for 9C obtained asdescribed above.

EXAMPLE 2C(2S)-2-((S)-Phenyl}[2-(thiomethyl)phenyl]thiol}methyl)morpholine (11C)(2S)-2-[(S)-{[2-(methylthio)phenyl]thio}(phenyl)methyl]-4-(phenylmethyl)morpholine(10C)

Compound 10C was obtained from 5Ca (4.0 g, 11.55 mmol),2-methylsulphenyl-thiophenol (2.17 g, 13.86 mmol, 1.2 eq) and caesiumcarbonate (4.42 g, 13.63 mmol, 1.18 eq) in dimethylformamide (35 ml)following a modification of General Procedure 1C in which the mixturewas heated at 50° C. for 1.5 hours, allowed to cool to room temperature,taken up in methanol and treated with SCX-2 (100 g). The SCX-2 waswashed with methanol. 10C was obtained as a white solid (4.92 g) afterSCX chromatography (eluent: ammonia/methanol 1/1 [v/v]) and removal ofsolvents in vacuo. Purification by flash column chromatography (eluent:ethyl acetate/isohexane gradient 10/90 to 30/70 [v/v]) gave 10C as awhite solid (4.04 g, 83%); MW 421.63; C₂₇H₂₇NOS₂; ¹H NMR (CDCl₃):7.03-7.15 (6H, m), 6.93-6.99 (2H, m), 6.74 (1H, td, 7 Hz, 1 Hz), 4.31(1H, d, 8 Hz), 3.95 (1H, br, d, 12 Hz), 3.83 (1H, td, 8 Hz, 3.8 Hz),3.59 (1H, td, 11 Hz and 3 Hz), 2.82 (1H, td, 12 Hz and Hz), 2.61-2.75(3H, m), 2.35 (3H, s), 1.73 (1H, br, s); LCMS (6 minute method): m/z 422[M+H]+@Rt 3.36 min.

(2S)-2-((S)-Phenyl{[2-(trifluoromethyl)phenyl]thio}methyl)morpholine(11C)

Compound 11C (Example 2C) was obtained from 10C (4.02 g, 9.53 mmol),solid supported Hünig's base (Argonaut, 3.56 mmol/g, 5.02 g, 17.87 mmol,2 eq) and α-chloroethyl chloroformate (3.09 ml, 28.6 mmol, 3 eq) inanhydrous dichloromethane (75 ml) following General Procedure 2Ca. Themixture was heated at 40° C. for 1.5 hours then left to stir at roomtemperature overnight. The reaction mixture was filtered andconcentrated in vacuo to give a pale orange liquid. This was taken up inmethanol (70 ml) and heated at 40° C. for 2 hours. A white solid crashedout of the solution which was taken up in methanol and purified by SCXchromatography (eluent: ammonia/methanol 1/1 [v/v]). After evaporationin vacuo 11C was obtained as a pale yellow oil (3.13 g, 99%); MW 331.50;C₁₈H₂₁NOS₂; ¹H NMR (CDCl₃): 7.03-7.15 (6H, m), 6.93-6.99 (2H, m), 6.74(1H, td, 7 Hz, 2 Hz), 4.31 (1H, d, 8 Hz), 3.95 (1H, br, d, 12 Hz), 3.83(1H, td, 8 Hz, 4 Hz), 3.59 (1H, td, 11 Hz, 3 Hz), 2.82 (1H, td, 12 Hz, 3Hz), 2.61-2.75 (3H, m), 2.35 (3H, s), 1.73 (1H, br, s). Compound 11C wasconverted into its hydrochloride salt following a modification ofGeneral Procedure 3C in which the pale yellow oil was taken up inisopropanol (˜200 ml) and filtered. Addition of hydrogen chloride (19 mlof a 1M solution in diethyl ether, 19 mmol) gave a white precipitate towhich further diethyl ether (˜50 ml) was added. The solid was isolatedby filtration and washed with diethyl ether to give the hydrochloridesalt of 11C as a white solid (3.03 g, 78%); MW 367.96; C₁₈H₂₂ClNOS₂; ¹HNMR (CDCl₃): 9.94 (2H, br, s), 7.06-7.18 (6H, m), 6.94-7.03 (2H, m),6.78 (1H, t, 7 Hz), 4.24-4.32 (1H, m), 4.20 (1H, d, 6 Hz), 3.89-4.06(2H, m), 3.18 (2H, br, t, 12 Hz), 2.99 (2H, br, s), 2.37 (3H, s); LCMS(10 minute method): m/z 332 [M−HCl]+@Rt 5.07 min.

EXAMPLE 3C(2S)-2-[(S)-{[2-(1-methylethyl)phenyl]thio}(phenyl)methylmorpholine(13C)(2S)-2-[(S)-{[2-(1-methylethyl)phenyl]thio}(phenyl)methyl]-4-(phenylmethyl)morpholine(12C)

Compound 12C was obtained from 5Ca (4.04 g, 11.66 mmol),2-isopropylsulphenyl-thiophenol (2.35 ml, 14 mmol, 1.2 eq) and caesiumcarbonate (4.56 g, 14 mmol, 1.2 eq) in dimethylformamide (35 ml)following a modification of General Procedure 1C in which the mixturewas heated at 90° C. for 20 minutes, allowed to cool to roomtemperature, taken up in ethyl acetate (50 ml), washed with water andbrine, dried over sodium sulphate, filtered and reduced in vacuo to givea yellow oil which was purified by SCX chromatography (eluent:ammonia/methanol 1/1 [v/v]). Removal of solvents in vacuo gave 12C as awhite solid (4.45, 91%); MW 417.62; C₂₇H₃₁NOS; ¹H NMR (CDCl₃): 7.14-7.26(7H, m), 7.03-7.1 (6H, m), 6.86-6.92 (1H, m), 4.10 (1H, d, 8 Hz),3.88-3.94 (2H, m), 3.62 (1H, td, 11 Hz, 2 Hz), 3.37-3.47 (2H, m), 3.22(1H, d, 13 Hz), 2.50 (2H, d, 11 Hz), 2.12-2.29 (2H, m), 1.05 (3H, d, 7Hz), 0.92 (3H, d, 7 Hz); LCMS (6 minute method): m/z 418 [M+H]+@Rt 3.72min.

(2S)-2-[(S)-{[2-(1-methylethyl)phenyl]thio}(phenyl)methyl]morpholine(13C)

Compound 13C (Example 3C) was obtained from 12C (4.44 g, 10.65 mmol),solid supported Hünig's base (Argonaut, 3.56 mmol/g, 6.05 g, 21.54 mmol,2 eq) and α-chloroethyl chloroformate (3.30 ml, 32.0 mmol, 3 eq) inanhydrous dichloromethane (50 ml) following General Procedure 2Ca. Themixture was heated at 40° C. for 1.5 hours then left to stir at roomtemperature overnight. The reaction mixture was filtered andconcentrated in vacuo to give a pale yellow liquid. This was taken up inmethanol (50 ml) and heated at 60° C. for 1.5 hours. The reactionmixture was allowed to cool to room temperature and purified by SCXchromatography (eluent: ammonia/methanol 1/1 [v/v]) to give 13C as apale yellow oil; MW 327.49; C₂₀H₂₅NOS; ¹H NMR (CDCl₃): 7.22 (1H, d, 8Hz), 7.03-7.13 (7H, m), 6.87-6.92 (1H, m), 4.04 (1H, d, 8 Hz), 3.94-3.99(1H, m), 3.79 (1H, td, 9 Hz, 3 Hz), 3.61 (1H, td, 11 Hz, 3 Hz), 3.41(1H, sept., 7 Hz), 2.82 (1H, td, 12 Hz and 3 Hz), 2.72 (1H, br, d, 12Hz), 2.52-2.63 (2H, m), 1.70 (1H, br, s), 1.05 (3H, d, 7 Hz), 0.91 (3H,d, 7 Hz). Compound 13C was converted into its hydrochloride saltfollowing a modification of General Procedure 3C in which the paleyellow oil was taken up in ether (50 ml), and filtered. Addition ofhydrogen chloride in dry diethyl ether (19 ml of a 1M solution indiethyl ether) gave a white precipitate to which further diethyl ether(50 ml) was added. The reaction mixture was concentrated and the residuewashed with diethyl ether to give a white solid (2.76 g, 69% overallyield from 5Ca); MW 363.95; C₂₀H₂₅NOS.HCl; ¹H NMR (CDCl₃): 9.91 (2H, br,s), 7.05-7.22 (7H, m), 6.91-6.96 (2H, m), 4.23-4.31 (1H, m), 4.08-3.90(3H, m), 3.31-3.41 (1H, m), 3.04-3.21 (2H, br, m), 2.91-2.99 (2H, br,m), 1.06 (3H, d, 7 Hz), 0.93 (3H, d, 7 Hz); LCMS (10 minute method): m/z327 [M−HCl]+@Rt 5.7 min.

EXAMPLE 4C(2S)-2-[(S)-([1,1′-Biphenyl]-2-ylthio)(phenyl)methyl]morpholine (15C)(2S)-2-[(S)-([1,1′-Biphenyl]-2-ylthio)(phenyl)methyl]-4-(phenylmethyl)morpholine(14C)

Compound 14C was obtained from 5Ca (2.16 g, 6.24 mmol),2-phenylsulphenyl-thiophenol (2.35 ml, 14 mmol, 1.2 eq) and caesiumcarbonate (2.43 g, 7.5 mmol, 1.2 eq) in dimethylformamide (50 ml)following a modification of General Procedure 1C in which the mixturewas heated at 90° C. for 20 minutes, allowed to cool to roomtemperature, taken up in ethyl acetate (50 ml), washed with water andbrine, dried over sodium sulphate, filtered and reduced in vacuo to givea yellow oil. Purification by SCX-chromatography (eluent:ammonia/methanol 1/1 [v/v]) followed by evaporation in vacuo gave 14C asa white solid (0.59 g, 90%); MW 451.64; C₃₀H₂₉NOS; ¹H NMR (CDCl₃):6.93-7.34 (19H, m), 3.92 (1H, br, d, 6 Hz), 3.63-3.76 (2H, m), 3.45 (1H,t, 10 Hz), 3.33 (1H, d, 13 Hz), 3.17 (1H, d, 12 Hz), 2.39 (1H, d, 12Hz), 2.20 (1H, d, 11 Hz), 1.97-2.07 (1H, m), 1.82-1.92 (1H, m); LCMS (6minute method): m/z 452 [M+H]+@Rt 3.69 min.

(2S)-2-[(S)-([1,1′-Biphenyl]-2-ylthio)(phenyl)methyl]morpholine (15C)

Compound 15C (Example 4C) was obtained from 14C (2.95 g, 6.54 mmol),solid supported Hünig's base (Argonaut, 3.56 mmol/g, 13.06 g, 21.54mmol, 2 eq) and α-chloroethyl chloroformate (2.0 ml, 19.6 mmol, 3 eq) inanhydrous dichloromethane (50 ml) following General Procedure 2Ca. Thereaction mixture was concentrated in vacuo to give a pale yellow liquid.This was taken up in methanol (70 ml) and heated at 40° C. for 2 hours.A white solid crashed out of the solution which was taken up in methanoland purified by SCX-chromatography (eluent: ammonia/methanol 1/1 [v/v]).After removal of solvents in vacuo 15C was obtained as a pale yellowoil; MW 361.51; C₂₃H₂₃NOS; ¹H NMR (CDCl₃): 7.0-7.45 (14H, m), 3.95 (1H,d, 8 Hz), 3.65-3.85 (2H, m), 3.35 (1H, d, 12 Hz), 3.2 (1H, d, 12 Hz),2.45 (1H, d, 10 Hz), 2.20 (1H, d, 10 Hz), 2.0-2.15 (1H, m), 1.8-2.0 (1H,m); LCMS (12 minute method): m/z 363 [M+H]+@Rt 3.00 min. 15C wasconverted into its hydrochloride salt following a modification ofGeneral Procedure 3C in which the pale yellow oil was taken up inisopropanol (˜200 ml), and filtered. Addition of hydrogen chloride (19ml of a 1M solution in diethyl ether) gave a white precipitate to whichfurther diethyl ether (˜50 ml) was added. The solid was isolated byfiltration and washed with diethyl ether to give the hydrochloride saltof 15C as a white solid (1.95 g, 75% overall yield from 5Ca); MW 397.97;C₂₃H₂₃NOS.HCl; ¹H NMR (CDCl₃): 9.80 (2H, br, s), 7.38-7.03 (12H, m),6.90-6.96 (2H, m), 3.85-4.00 (2H, m), 3.72-3.82 (1H, m), 3.66 (1H, d, 5Hz), 2.98-3.10 (1H, m), 2.81 (1H, br, s), 2.62 (2H, br, s); LCMS (12minute method): m/z 362 [M+H]+@Rt 2.99 min.

EXAMPLE 5C (2S)-2-[(S)-[(2-Fluorophenyl)thio](phenyl)methyl]morpholine(17C)(2S)-2-[(S)-[(2-Fluorophenyl)thio](phenyl)methyl]-4-phenylmethyl)morpholine(16Ca) and(2R)-2-[(R)-[(2-Fluorophenyl)thio](phenyl)methyl]-4-phenylmethyl)morpholine(16Cb)

Compounds 16Ca,16Cb were obtained from 5Ca,5Cb (0.114 g, 0.33 mmol),2-fluorothiophenol (0.045 g, 0.36 mmol, 1.2 eq) and caesium carbonate(0.12 g, 0.36 mmol, 1.2 eq) in dimethylformamide (50 ml) followingGeneral Procedure 1C as a pale yellow oil (0.14 g, 65%); MW 393.53;C₂₄H₂₄FNOS; ¹H NMR (CDCl₃): 7.12-7.36 (12H, m), 6.87-6.99 (2H, m), 4.48(1H, d, 8 Hz), 4.00-4.11 (2H, m), 3.77 (1H, td, 11 Hz, 2 Hz), 3.60 (1H,d, 13 Hz), 3.37 (1H, d, 13 Hz); 2.63 (2H, t, 10 Hz), 2.16-2.31 (2H, m);LCMS (2.5 minute method): m/z 394 [M+H]⁺@R_(t) 1.41 min.

(2S)-2-[(S)-[(2-Fluorophenyl)thio](phenyl)methyl]morpholine (17C)

Compound 17C (Example 5C) was obtained from 16Ca,16Cb (0.72 g, 0.18mmol), solid supported Hünig's base (Argonaut, 3.56 mmol/g, 2.0 g, 0.56mmol, 3 eq) and α-chloroethyl chloroformate (0.62 ml, 0.56 mmol, 3 eq)in anhydrous dichloromethane (5 ml) following General Procedure 2Ca as aviscous yellow oil (0.046 g, 82%) from which 17C was obtained as asingle isomer after separation by chiral HPLC (0.016 g); Chiral LC (AD):10.83 min. LC purity=91% (UV254 nm)/98% (ELS); LCMS (10 minute method):m/z 304 [M+H]+@Rt 5.82 min; HPLC purity=84% (UV215 nm)/98% (ELS); MW303.41; C₁₇H₁₈FNOS; ¹H NMR (CDCl₃): 7.13-7.00 (7H, m), 6.87-6.76 (2H,m), 4.29 (1H, d, 9 Hz), 3.98-3.93, (1H, m), 3.78 (1H, td, 9 Hz and 4Hz), 3.60 (1H, td, 11 Hz and 3 Hz), 2.82 (1H, td, 12 Hz, 3 Hz),2.76-2.70 (1H, m), 2.57-2.53, (2H, m), NH signal not observed; LCMS (10minute method): m/z 304 [M+H]+@Rt 5.84 min; HPLC purity=100%% (ELS).Compound 17C was converted into its hydrochloride salt following GeneralProcedure 3C.

EXAMPLE 6C (2S)-2-[(S)-[(2-Ethylphenyl)thio](phenyl)methyl]morpholine(19C)(2S)-2-[(S)-[(2-Ethylphenyl)thio](phenyl)methyl]-4-(phenylmethyl)morpholine(18Ca) and(2R)-2-[(R)-[(2-Ethylphenyl)thio](phenyl)methyl]-4-(phenylmethyl)morpholine(18Cb)

Compounds 18Ca,18Cb were obtained from 5Ca,5Cb (0.2 g, 0.58 mmol),2-ethyl-thiophenol (0.16 g, 1.16 mmol, 2 eq) and caesium carbonate (0.23g, 0.7 mmol, 1.2 eq) in dimethylformamide (5 ml) following modificationof General Procedure 1C in which the reaction mixture was heated to 95°C. for 2 hours. After purification by flash column chromatography(eluent: ethyl acetate/hexane 9/1 [v/v]) 18Ca,18Cb was obtained as awhite solid (0.15 g, 65%%); MW 403.59; C₂₆H₂₉NOS; ¹H NMR (CDCl₃):6.96-7.40 (14H, m), 4.22 (1H, d, 7 Hz), 3.96-4.01 (2H, m), 3.72 (1H, td,11 Hz and 2 Hz), 3.52 (1H, d, 13 Hz), 3.32 (1H, d, 13 Hz), 2.68 (2H, q,8 Hz), 2.59 (2H, br d, 12 Hz), 2.06-2.21 (2H, m), 1.12 (3H, t, 7 Hz);LCMS (2.5 minute method) m/z 404 [M+H]+@Rt 1.49 min.

(2S)-2-[(S)-[(2-Ethylphenyl)thio](phenyl)methyl]morpholine (19C)

Compound 19C (Example 6C) was obtained from 18Ca,18Cb (0.18 g, 0.52mmol), solid supported Hünig's base (Argonaut, 3.56 mmol/g, 3.7 g, 1.04mmol, 2 eq) and α-chloroethyl chloroformate (0.34 ml, 3.12 mmol, 3 eq)in anhydrous dichloromethane (5 ml) following General Procedure 2Ca as aviscous yellow oil (0.21 g, 86%) from which 19C was obtained afterseparation by chiral HPLC on chiral OD semi-preparative column; chiralLC (OD): 15.95 min. LC purity=100% (UV254 nm)/100% (ELS); MW 313.47;C₁₉H₂₃NOS; ¹H NMR (CDCl₃): 7.17 (1H, d, 8 Hz), 7.12-7.05 (5H, m), 7.01(2H, d, 4 Hz), 6.87-6.93 (1H, m), 4.07 (1H, d, 8 Hz), 3.92-3.97 (1H, m),3.74-3.80 (1H, m), 3.59 (1H, td, 11 Hz, 3 Hz), 2.80 (1H, td, 12 Hz and 3Hz), 2.71 (1H, br, d, 12 Hz), 2.63-2.54 (4H, m), 1.64 (1H, br, s), 1.04(3H, t, 8 Hz); LCMS (10 minute method): m/z 314 [M+H]+@Rt 5.92 min. 19Cwas converted into its hydrochloride salt following General Procedure3C; MW 349.93; C₁₉H₂₃NOS.HCl; ¹H NMR (CDCl₃): 10.10 (2H, br, s),7.13-7.28 (8H, m), 7.02-7.08 (1H, m), 4.36 (1H, br, s), 4.01-4.17 (3H,br, m), 3.16-3.31 (2H, br, m), 2.92-3.09 (2H, br, m), 2.71 (2H, q, 8Hz), 1.15 (3H, t, 7 Hz).

EXAMPLE 7C(2S)-2-[(S)-{[2-(Methyloxy)phenyl]thio}(phenyl)methyl]morpholine (21C)(2S)-2-[(S)-{[2-(Methyloxy)phenyl]thio}(phenyl)methyl]-4-(phenylmethyl)morpholine(20Ca) and(2R)-2-[(R)-{[2-(Methyloxy)phenyl]thio}(phenyl)methyl]-4-(phenylmethyl)morpholine(20Cb)

Compounds 20Ca,20Cb were obtained from 5Ca,5Cb (0.18 g, 0.52 mmol),2-methoxy thiophenol (0.074 ml, 0.57 mmol, 1.2 eq) and caesium carbonate(0.17 g, 0.52 mmol, 1.2 eq) in dimethylformamide (5 ml) followingmodification of General Procedure 1C in which the reaction was heated at95° C. for 2.5 hours. After purification by flash column chromatography(eluent: ethyl acetate/hexane gradient 15/85 to 25/75 [v/v]) 20Ca,20Cbwas obtained as a viscous yellow oil (0.17 g, 83%); MW 405.56;C₂₅H₂₇NO₂S; ¹H NMR (CDCl₃): 7.01-7.26 (12H, m), 6.58-6.63 (2H, m), 4.39(1H, d, 7 Hz), 3.86-3.91 (2H, m), 3.71 (3H, s), 3.56-3.62 (1H, m), 3.42(1H, d, 11 Hz); 3.21 (1H, d, 11 Hz), 2.46-2.52 (2H, m), 2.01-2.11 (2H,m); LCMS (10 minute method): m/z 406 [M+H]⁺@R_(T) 6.09 min.

(2S)-2-[(S)-{[2-(Methyloxy)phenyl]thio}(phenyl)methyl]morpholine (21C)

Compound 21C (Example 7C) was obtained from 20Ca,20Cb (0.1 g, 0.25mmol), solid supported Hünig's base (Argonaut, 3.56 mmol/g, 1.78 g, 0.5mmol, 2 eq) and α-chloroethyl chloroformate (0.16 ml, 1.5 mmol, 3 eq) inanhydrous dichloromethane (5 ml) following General Procedure 2Ca as aviscous yellow oil (0.06 g, 77%) from which 21C was obtained afterseparation by chiral HPLC on a Chiralcel OJ semi-preparative column.Chiral LC: 11.45 min. LC purity=100%; MW 315.44; C₁₈H₂₁NO₂S; ¹H NMR(CDCl₃): 7.14-7.34 (7H, m), 6.74-6.84 (2H, m), 4.50 (1H, d, 8 Hz), 4.10(1H, d, 11 Hz), 3.85-4.00 (4H, m), 3.74 (1H, dt, 1 Hz, 11 Hz), 2.82-3.02(2H, m), 2.66-3.02 (3H, m); LCMS (10 minute method): m/z 316[M+H]⁺@R_(t) 4.87 min. 21C was converted its hydrochloride saltfollowing General Procedure 3C.

EXAMPLE 8C(2S)-2-[(S)-({2-[(1-Methylethyl)oxy]phenyl}thio)(phenyl)methyl]morpholine(23C)(2S)-2-[(S)-({2-[(1-Methylethyl)oxy]phenyl}thio)(phenyl)methyl]-4-(phenylmethyl)morpholine(22Ca) and(2R)-2-[(R)-({2-[(1-Methylethyl)oxy]phenyl}thio)(phenyl)methyl]-4-(phenylmethyl)morpholine(22Cb)

Compounds 22Ca,22Cb were obtained from 5Ca,5Cb (0.57 g, 1.7 mmol),2-isopropoxy-thiophenol (0.94 g, 5.61 mmol) and caesium carbonate (2.18g, 6.72 mmol, 1.2 eq) in dimethylformamide (15 ml) followingmodification of General Procedure 1C in which the reaction mixture washeated to 95° C. for 3 hours. After purification by SCX chromatography(eluent: ammonia/methanol 1/1 [v/v]) 22Ca,22Cb was obtained as a darkyellow oil (0.56 g, 76%%); MW 433.62; C₂₇H₃₁NO₂S; ¹H NMR (CDCl₃):7.01-7.24 (7H, m), 6.94-7.09 (5H, m), 6.64 (1H, d, 8 Hz), 6.56 (1H, td,8 Hz, 1 Hz), 4.42-4.51 (2H, m), 3.83-3.92 (2H, m), 3.56 (1H, td, 11 Hzand 3 Hz), 3.42 (1H, d, 13 Hz), 3.24 (1H, d, 13 Hz), 2.52 (1H, d, 11Hz), 2.46 (1H, d, 11 Hz), 2.05-2.17 (2H, m), 1.29 (3H, d, 6 Hz), 1.27(3H, d, 6 Hz); LCMS (2.5 minute method): m/z 434 [M+H]⁺@R_(T) 1.44 min.

(2S)-2-[(S)-({2-[(1-Methylethyl)oxy]phenyl}thio)(phenyl)methyl]morpholine(23C)

Compound 23C (Example 8C) was obtained from 22Ca,22Cb (0.56 g, 1.3mmol), solid supported Hünig's base (Argonaut, 3.56 mmol/g, 0.73 g, 2.6mmol, 2 eq) and a-chloroethyl chloroformate (0.16 ml, 1.5 mmol, 3 eq) inanhydrous dichloromethane (5 ml) following General Procedure 2Ca as aviscous yellow oil (0.41 g, 93%) after separation using chiral HPLC on aOD semi-preparative column. Chiral LC (OD): 12.51 min. LC purity=100%(UV254 nm)/100% (ELS); MW 343.49; C₂₀H₂₅NO₂S; ¹H NMR (CDCl₃): 7.13-7.20(1H, m), 6.96-7.12 (6H, m), 6.67 (1H, d, 8 Hz), 6.59 (1H, td, 7 Hz, 1Hz), 4.48 (1H, sept., 6 Hz), 4.38 (1H, d, 7 Hz), 3.90-3.95 (1H, m), 3.73(1H, td, 8 Hz, 4 Hz), 3.54 (1H, td, 11 Hz and 3 Hz), 2.79 (1H, td, 12 Hzand 3 Hz), 2.62-2.72 (3H, m), 1.55 (1H, br, s), 1.32 (3H, d, 6 Hz), 1.29(3H, d, 6 Hz); LCMS (10 minute method): m/z 344 [M+H]+@Rt 6.19 min; HPLCpurity=92% (UV215nm). 23C was converted into its hydrochloride saltfollowing General Procedure 3C; MW 379.95; C₂₀H₂₅NO₂S.HCl; ¹H NMR(CDCl₃): 9.81-10.04 (2H, br, m), 7.03-7.25 (7H, m), 6.71 (1H, d, 8 Hz),6.63 (1H, t, 7 Hz), 4.51 (1H, sept., 6 Hz), 4.31 (1H, d, 6 Hz),4.15-4.23 (1H, m), 3.83-4.03 (2H, m), 3.05-3.18 (2H, m), 2.80-3.03 (2H,m), 1.31 (3H, d, 6 Hz), 1.29 (3H, d, 6 Hz).

EXAMPLE 9C 2-{[(S)-(2S)-Morpholin-2-yl(phenyl)methyl]thio}phenyltrifluoromethyl ether (25C)(2S)-4-(Phenylmethyl)-2-[(S)-phenyl({2-[(trifluoromethyl)oxy]phenyl}thio)methyl]morpholine(24Ca) and(2S)-4-(Phenylmethyl)-2-[(S)-phenyl({2-[(trifluoromethyl)oxy]phenyl}thio)methyl]morpholine(24Cb)

Compounds 24Ca,24Cb were obtained from 5Ca,5Cb (0.01 1 g, 0.33 mmol),2-trifluoromethoxythiophenol (1.2 eq, 0.077 g, 0.39 mmol) and caesiumcarbonate (0.15 g, 0.47 mmol, 1.2 eq) in dimethylformamide (15 ml)following modification of General Procedure 1C in which the reaction washeated at 95° C. for 1.5 hours. The reaction mixture was allowed to coolto room temperature, diluted with ethyl acetate (20 ml), washedsequentially with water and brine, dried over sodium sulphate andfinally concentrated in vacuo to give a pale yellow oil (0.14 g, 92%);MW 459.53; C₂₅H₂₄F₃NO₂S; ¹H NMR (CDCl₃): 7.13-7.41 (13H, m), 7.08-7.13(1H, m), 4.51 (1H, d, 8 Hz), 3.99-4.07 (2H, m), 3.73 (1H, td, 9 Hz, 2.5Hz), 3.57 (1H, d, 13 Hz), 3.37 (1H, d, 13 Hz); 2.57-2.66 (2H, m),2.20-2.31 (2H, m); LCMS (10 minute method): m/z 460 [M+H]⁺@R_(t) 6.69min.

2-{[(S)-(2S)-Morpholin-2-yl(phenyl)methyl]thio}phenyl trifluoromethylether (25C)

Compound 25C (Example 9C) was obtained from 24Ca,24Cb (0.06 g, 0.13mmol), solid supported Hünig's base (Argonaut, 3.56 mmol/g, 0.073 g,0.026 mmol, 2 eq) and α-chloroethyl chloroformate (0.04 ml, 0.39mmol, 3eq) in anhydrous dichloromethane (5 ml) following General Procedure 2Caas a viscous yellow oil (0.021 g, 44%) from which 25C was obtained afterseparation using chiral HPLC on a OD semi-preparative column. Chiral LC(OJ): 12.60 min. LC purity=98% (UV_(254 nm))/100% (ELS); MW 369.41;C₁₈H₁₈F₃NO₂S; ¹H NMR (CDCl₃): 7.02-7.21 (8H, m), 6.91-6.96 (1H, m), 4.28(1H, d, 8 Hz), 3.93 (1H, br, d 11 Hz), 3.75-3.81 (1H, m), 3.60 (1H, td,11 Hz and 3 Hz), 2.71-2.86 (2H, m), 2.61 (2H, d, 6 Hz), 1.90 (1H br, s);LCMS (10 minute method): m/z 370 [M+H]⁺@R_(t) 5.86 min.

EXAMPLE 10C: (2S)-2-[(S)-[(2-Methylphenyl)thio](phenyl)methyl]morpholine(27C)(2S)-2-[(S)-[(2-Methylphenyl)thio](phenyl)methyl]-4-(phenylmethyl)morpholine(26Ca) and(2R)-2-[(R)-[(2-Methylphenyl)thio(phenyl)methyl]-4-(phenylmethyl)morpholine(26Cb)

Compounds 26Ca,26Cb were obtained from 5Ca,5Cb (0.1 g, 0.29 mmol),2-methyl thiophenol (0.04 ml, 0.31 mmol) and caesium carbonate (0.125 g,0.37 mmol, 1.2 eq) in dimethylformamide (15 ml) following GeneralProcedure 1C as a colourless oil (0.13 g, 85%); MW 389.56; C₂₅H₂₇NOS; ¹HNMR (CDCl₃): 6.84-7.24 (14H, m), 4.14 (1H, d, 8 Hz), 3.85-3.95 (2H, m),3.60 (1H, dt, 10 Hz, 3 Hz), 3.42 (1H, d, 13 Hz); 3.21 (1H, d, 13 Hz),2.46-2.54 (2H, m), 2.18 (3H, s), 1.97-2.13 (2H, m); LCMS (2.5 minutemethod): m/z 390 [M+H]⁺@R_(T) 1.49 min.

(2S)-2-[(S)-[(2-Methylphenyl)thio](phenyl)methyl]morpholine (27C)

Compound 27C (Example 10C) was obtained from 26Ca,26Cb (0.04 g, 0.12mmol), solid supported Hünig's base (Argonaut, 3.56 mmol/g, 0.89 g, 0.24mmol, 2 eq) and α-chloroethyl chloroformate (0.04 ml, 0.36mmol, 3 eq) inanhydrous dichloromethane (5 ml) following General Procedure 2Ca as aviscous yellow oil (0.03 g, 75%) from which 27C was obtained afterchiral separation. Chiral LC (OJ): 15.84 min. LC purity=98.57%(UV_(254 nm)); MW 299.44; C₁₈H₂₁NOS; ¹H NMR (CDCl₃): 6.86-7.21 (9H, m),4.08 (1H, d, 7 Hz), 3.75 (1H, br s), 3.58 (1H, br s), 2.34-3.1 (4H, m),2.20 (3H, s); 1.41-2.04 (2H, m); LCMS (10 minute method): m/z 300[M+H]⁺@R_(T) 5.08 min. 27C was converted into its hydrochloride saltfollowing General Procedure 3C.

EXAMPLE 11C (2S)-2-{(S)-Phenyl[(2-propylphenyl)thio]methyl}morpholine(29C)(S)-Phenyl[(2S)-4-(phenylmethyl)morpholin-2-yl]methyl-2-propylphenylsulfide (28Ca) and(R)-Phenyl[(2R)-4-(phenylmethyl)morpholin-2-yl]methyl-2-propylphenylsulfide (28Cb)

Compounds 28Ca,28Cb were obtained from 5Ca (0.53 g, 1.50 mmol),2-n-propyl thiophenol (0.025 g, 1.65 mmol) and caesium carbonate (0.59g, 1.8 mmol, 1.2 eq) in dimethylformamide (5 ml) following amodification of General Procedure 1C in which the reaction was heated at95° C. for 3 hours. After purification by SCX column chromatography(eluent: ammonia/methanol 1/1 [v/v]) 28Ca,28Cb was obtained as a darkyellow oil (0.56 g, 90%%); MW 417.62; C₂₇H₃₁NOS; ¹H NMR (CDCl₃):7.23-7.12 (6H, m), 7.06-7.11 (5H, m), 6.97-6.99 (2H, m), 6.87-6.92 (1H,m), 4.13 (1H, d, 8 Hz), 3.86-3.94 (2H, m), 3.61 (1H, td, 11 Hz, 2 Hz),3.44 (1H, d, 13 Hz), 3.23 (1H, d, 13 Hz), 2.46-2.59 (4H, m), 2.01-2.14(2H, m), 1.34-1.52 (2H, m), 0.83 (3H, t, 7 Hz); LCMS (2.5 minutemethod): m/z 418 [M+H]⁺@R_(t) 1.55 min.

(2S)-2-{(S)-Phenyl[(2-propylphenyl)thio]methyl}morpholine (29C)

Compound 29C (Example 11C) was obtained from 28Ca,28Cb (0.56 g, 1.35mmol), solid supported Hünig's base (Argonaut, 3.56 mmol/g, 0.75 g, 2.7mmol, 2 eq) and α-chloroethyl chloroformate (0.44 ml, 4.05 mmol, 3 eq)in anhydrous dichlorometbane (5 ml) following General Procedure 2Ca as aviscous yellow oil (0.41 g, 93%); MW 327.49; C₂₀H₂₅NOS; ¹H NMR (CDCl₃):7.17 (1H, br, d, 7 Hz), 7.07-7.12 (5H, m), 6.96-7.00 (2H, m), 6.88-6.93(1H, m), 4.07 (1H, d, 8 Hz), 3.93-3.98 (1H, m), 3.74-3.80 (1H, m), 3.60(1H, td, 11 Hz, 3 Hz), 2.81 (1H, td, 12 Hz and 3 Hz), 2.72 (1H, br, d,12 Hz), 2.48-2.62 (4H, m), 1.36-1.59 (3H, m), 0.83 (3H, t, 7 Hz); LCMS(2.5 minute method): m/z 328 [M+H]⁺@R_(t) 1.40 min (single major peak).

EXAMPLE 12C Methyl2-{[(S)-(2S)-morpholin-2-yl(phenyl)methyl]thio}benzoate (31C)Methyl-2-({(S)-phenyl[(2S)-4-(phenylmethyl)morpholin-2-yl]methyl}thio)benzoate(30Ca) andMethyl-2-({(R)-phenyl[(2R)-4-(phenylmethyl)morpholin-2-yl]methyl}thio)benzoate(30Cb)

Compounds 30Ca,30Cb were obtained from 5Ca,5Cb (0.5 g, 1.45 mmol),methyl thiosalicylate (0.49 g, 2.89 mmol) and potassium carbonate (0.21g, 1.52 mmol) in dry tetrahydrofurane (5 ml) following modification ofGeneral Procedure 1C in which the solvents were degassed and purged withnitrogen before the addition of methyl thiosalicylate. The reactionmixture was stirred at room temperature for 18 hours after which timethe reaction mixture was poured onto water and extracted twice withdiethyl ether. The organic layers were washed with water, dried andevaporated in vacuo. After purification by SCX column chromatography(eluent: ammonia/methanol 1/1 [v/v]) 30Ca,30Cb was obtained as acolourless solid (0.18 g, 29%%); MW 433.57; C₂₆H₂₇NO₃S; ¹H NMR (CDCl₃):8.65-8.85 (1H, m), 6.95-7.45 (13H, m), 4.45 (1H, d, 8 Hz), 3.85-4.05(1H, m), 3.8 (3H, s), 3.65 (1H, dt, 1 Hz and 7 Hz), 3.55 (1H, d, 11 Hz),3.25 (1H, d, 11 Hz), 2.5-2.6 (2H, m); 2.0-2.15 (2H, m); FIA: m/z 462[M+H]⁺.

Methyl 2-{[(S)-(2S)-morpholin-2-yl(phenyl)methyl]thio}benzoate (31C)

Compound 31C (Example 12C) was obtained from 30Ca,30Cb (0.2 g, 0.46mmol), solid supported Hünig's base (Argonaut, 3.56 mmol/g, 0.08 g, 2.77miol, 6 eq) and α-chloroethyl chloroformate (0.5 ml, 4.62 mmol, 10 eq)in anhydrous dichloromethane (5 ml) following General Procedure 2Ca as awhite solid (0.16 g, 91%) from which 31C was obtained after separationusing chiral HPLC on chiral OJ semi-preparative column. Chiral LC (OJ):12.32 min. LC purity=100% (UV_(254 nm)); MW 343.45. 31 was convertedinto its hydrochloride salt following General Procedure 3C; ¹H NMR(d₆-DMSO): 9.30-9.5 (1H, m), 7.75-7.80 (1H, m), 7.1-7.55 (8H, m), 4.82(1H, d, 8 Hz), 3.95-4.15 (2H, m), 3.65.3.9 (3H, m), 3.55 (3H, s),2.80-3.25 (2H, m).

EXAMPLE 13C(2S)-2-((S)-(3-Fluorophenyl){[2-(trifluoromethyl)phenyl]thio}methyl)morpholine(33C)(2S)-2-((S)-(3-Fluorophenyl){[2-(trifluoromethyl)phenyl]thio}methyl)-4-(phenylmethyl)morpholine(32Ca) and(2R)-2-((R)-(3-Fluorophenyl){[2-(trifluoromethyl)phenyl]thio}methyl)-4-(phenylmethyl)morpholine(32Cb)

Compounds 32Ca,32Cb were obtained as outlined in Scheme 5C from38Ca,38Cb (0.33 g, 0.91 mmol) following General Procedure 4C as a whitesolid after column chromatography (0.28 g, 67%); MW 461.53; C₂₅H₂₃F₄NOS;¹H NMR (CDCl₃) 6.75-7.65 (1H, m), 6.85-7.33 (12H, m), 4.45 (2H, d, 8Hz), 3.6-3.75 (2H, m), 3.45 (1H, d 12 Hz), 3.3 (1H, d 12 Hz), 2.45-2.7(2H, br, m), ), 2.1-2.3 (2H, br, m); FIA: m/z 462 [M+H]⁺.

(2S)-2-((S)-(3-Fluorophenyl){[2-(trifluoromethyl)phenyl]thio}methyl)morpholine(33C)

Compound 33C (Example 13C) was obtained from 32Ca,32Cb (0.28 g, 0.615mmol), solid supported Hünig's base (Argonaut, 3.56 mmol/g, 0.19 g, 0.68mmol, 1.1 eq) and α-chloroethyl chloroformate (0.07 ml, 0.68 mmol, 1.1eq) in anhydrous dichloromethane (5 ml) following General Procedure 2Caas a colourless oil (0.22 g, 95%) from which 33C was obtained afterchiral chromatography on a Chiralcel OJ semi-preparative column. ChiralLC (OJ): 13.33 min. LC purity=98.37% (UV_(254 nm)); MW 371.4;C₁₈H₁₇F₄NOS. LCMS (12 minute method): m/z 372 [M+H]+@ Rt 5.2 min. 33Cwas converted into its hydrochloride salt following General Procedure3C; MW 407.86; C₁₈H₁₇F₄NOS.HCl; ¹H NMR (CDCl₃) 9.8-10.2 (1H, br),7.4-7.6 (1H, m), (6.85-7.45 (8H, m), 4.05-4.45 (4H, br, m), 2.90-3.41(4H, br, m).

EXAMPLE 14C(2S)-2-((S)-(4-Chlorophenyl){[2-(trifluoromethyl)phenyl]thio}methyl)morpholine(35C)(2S)-2-((S)-(4-Chlorophenyl){[2-(trifluoromethyl)phenyl]thio}methyl)-4-(phenylmethyl)morpholine(34Ca) and(2R)-2-((R)-(4-Chlorophenyl){[2-(trifluoromethyl)phenyl]thio}methyl)-4-(phenylmethyl)morpholine(34Cb)

Compounds 34Ca,34Cb were obtained as outlined in Scheme 5C from39Ca,39Cb (0.4 g, 1.06 mmol, 1.1 eq), cesium carbonate (0.33 g, 1.0mmol, 1.1 eq), and 2-trifluoromethyl benzene thiol (0.19 g, 1.06 mmol,1.1 eq) following a modification of General Procedure 1C in which thereaction was stirred at room temperature for 1.5 hours as a white solidafter column chromatography (eluent: gradient hexane/ethyl acetate 10/90to 25/75[v/v]) (0.409 g, 80%); MW 477.98; C₂₅H₂₃F₃ClNOS; ¹H NMR (CDCl₃)7.1-7.65 (13H, m), 4.45 (1H, d, 8 Hz), 3.85-4.0 (2H, m), 3.55 (1H, m),3.3 (1H, d 12 Hz), 3.3 (1H, d 12 Hz), 2.45-2.65 (2H, br),), 2.1-2.3 (2H,br, m); FIA: m/z 478 [M+H]⁺.

(2S)-2-((S)-(4-Chlorophenyl){[2-(trifluoromethyl)phenyl]thio}methyl)morpholine(35C)

Compound 35C (Example 14C) was obtained from 34Ca,34Cb (0.41 g, 0.86mmol), solid supported Hünig's base (Argonaut, 3.56 mmol/g, 0.27 g, 0.94mmol, 1.1 eq) and α-chloroethyl chloroformate (0.10 ml, 0.94 mmol, 1.1eq) in anhydrous dichloromethane (5 ml) following General Procedure 2Caas a colourless oil (0.28 g, 84% yield) from which 35C was obtainedafter separation using chiral HPLC on a ChiralPak-AD OJ semi-preparativecolumn; MW 387.85; C₁₈H₁₇ClF₃NOS; LCMS (12 minute method): m/z 372[M+H]+@Rt 5.2 min. 35C was converted into its hydrochloride saltfollowing General Procedure 3C; MW 423.96; C₁₈H₁₇CIF₃NOS.HCl; ¹H NMR(CDCl₃): 9.8-10.2 (1H, br), 7.4-7.6 (1H, m), 7.07-7.35 (7H, m), 3.8-4.45(4H, br, m), 2.85-3.45 (4H, br, m).

EXAMPLE 15C(2S)-2-((S)-(2-Fluorophenyl){[2-(methyloxy)phenyl]thio}methyl)morpholine(37C)(2S)-2-((S)-(2-Fluorophenyl){[2-(methyloxy)phenyl]thio}methyl)-4-(phenylmethyl)morpholine(36Ca) and(2R)-2-((R)-(2-Fluorophenyl){[2-(methyloxy)phenyl]thio}methyl)-4-(phenylmethyl)morpholine(36Cb)

Compounds 36Ca,36Cb were obtained from 7Ca,7Cb (0.45 g, 1.17 mmol),cesium carbonate (0.42 g, 1.29 mmol, 1.1 eq), and 2-methoxy-thiophenol(0.82 g, 5.87 mmol) following a modification of General Procedure 1C inwhich the reaction mixture was heated to 95° C. for 2 hours and thenstirred at room temperature for 18 hours. After purification by flashcolumn chromatography (eluent: heptane/ethyl acetate 80/20 [v/v])36Ca,36Cb was obtained as a colourless oil (0.36 g, 72%%); MW 423.55;C₂₅H₂₆FNOS; ¹H NMR (CDCl₃): 6.65-7.5 (13H, m), 4.9 (1H, d, 7 Hz),3.9-4.05 (2H, m), 3.8 (3H, s), 3.6 (1H, dt, 8 Hz and 1 Hz), 3.45 (1H, d,13 Hz), 3.15 (1H, d, 13 Hz), 2.60 (2H, t, 8 Hz), 2.05-2.2 (2H, m); FIA:m/z 424 [M+H]⁺.

(2S)-2-((S)-(2-Fluorophenyl){[2-(methyloxy)phenyl]thio}methyl)morpholine(37C)

Compound 37C (Example 15C) was obtained from 36Ca,36Cb (0.43 g, 1.02mmol), solid supported Hünig's base (Argonaut, 3.56 mmol/g, 0.37 g, 1.12mmol, 1.1 eq) and α-chloroethyl chloroformate (1.08 ml, 10.12 mmol, 10eq) in anhydrous dichloromethane (5 ml) following General Procedure 2Caas a colourless oil (0.34 g, 99%) after separation by chiral HPLC on aChiralPak-AD semi-preparative column. Chiral LC: 12.86 min. LCpurity=99.1 (UV_(254 nm)); MW 369.89; C₁₈H₂₀FNOS; FIA: m/z 334 [M+H]⁺.37C was converted into its hydrochloride salt following GeneralProcedure 3C; MW 333.43; C₁₈H₂₀FNOS; ¹H NMR (CDCl₃): 7.2-7.3 (1H, m),6.85-7.2 (8H, m), 4.85 (1H, d, 8 Hz), 3.95-4.15 (2H, m), 3.85.3.9 (3H,m), 3.7 (1H, dt, 1 Hz and 7 Hz), 2.6-3.0 (4H, m).

EXAMPLE 16C2-12-Methyl-1-(2-trifluoromethyl-phenylsulfanyl)-propyl]-morpholine(56C) 4-Benzyl-2-(1-hydroxy-2-methyl-propyl)-morpholin-3-one (53C)

To a stirred solution of 2C (5.05 g, 26.4 mmol) in tetrahydrofuran (25ml) at −78° C. under nitrogen was added lithium diisopropylamide (14.5ml of a 2M solution, 29.0 mmol) dropwise over 40 minutes. The reactionmixture was stirred at the same temperature over 30 minutes after whichtime a solution of isobutyraldehyde (2.63 ml, 29.0 mmol) intetrahydrofuran (15 ml) was added dropwise over 30 minutes. After onehour, the reaction mixture was allowed to warm to room temperature andquenched by addition of saturated ammonium chloride solution. Extractionwith dichloromethane and drying over magnesium sulphate gave 53C as amixture of diastereomers. Upon concentration in vacuo one diastereomerprecipitated as a white solid (53Ca: 0.99 g). The remaining motherliquors were purified by column chromatography (30% ethyl acetate inhexane [v/v]) to give 53C (2.06 g). MW 263.34; C₁₅H₂₁NO₃; LCMS (6 minmethod): m/z 286 [M+Na]⁺; RT=2.748.

1-(4-Benzyl-morpholin-2-yl)-2-methyl-propan-1-ol (54C)

To a stirred solution of 53C (1.97 g, 7.47 mmol) in tetrahydrofuran (50ml) at room temperature under nitrogen was added borane-tetrahydrofurancomplex (30 ml of a 1M solution, ca 4 eq.). The reaction was heated to60° C. and followed by TLC-analysis. When all starting material had beenconsumed a few drops of methanol were added followed by a similar amountof 1N hydrochloric acid and heating was continued for another hour.Organic solvents were removed in vacuo and the remaining solution waspoured onto 1M potassium carbonate solution (30 ml), extracted withdiethyl ether. The organic layers were dried over magnesium sulphate andpurified by column chromatography (gradient from 15% ethyl acetate inhexane [v/v]) gave 54C (1.8 g, 97%). MW 249.36; C₁₅H₂₃NO₂; LCMS (6 minmethod): m/z 250 [M+H]⁺; RT=0.838.

4-Benzyl-2-[2-methyl-1-(2-trifluoromethyl-phenylsulfanyl)-propyl]-morpholine(55C)

Compound 55C was obtained from 54C in a two-step procedure. To a stirredsolution of 54C (1.8 g, 7.2 mmol) in dichloromethane (50 ml) at roomtemperature was added solid solid supported Hünig's base (Argonaut, 3.56mmol/g, 6.2 g, 22 mmol, 3 eq) followed methanesulphonyl chloride (1.12ml, 14 mmol). After stirring for one hour, the reaction mixture wasfiltered and the filtrates washed with brine and dried over magnesiumsulphate to give the intermediate mesylate as a yellow oil (2.93 g ofisolated crude product). The crude product was taken up in drydimethylformamide (50 ml), 2-trifluoromethyl benzenethiol (2.1 ml, 14mmol) and solid supported Hünig's base (Argonaut, 3.56 mmol/g, 0.55 g,1.95 mmol) were added and the mixture heated to 70° C. and stirred for72 hours. The reaction was quenched by addition of water (50 ml) andsodium hydroxide solution (70 ml of a 2N solution). The aqueous layerwas extracted with diethyl ether (3×50 ml), washed with brine and driedover magnesium sulphate. Purification by ion-exchange chromatographyfollowed by preparative HPLC gave 55C. MW 409.52; C₂₂H₂₆F₃NOS; LCMS (6min method): m/z 410 [M+H]⁺; RT=3.398.

2-[2-Methyl-1-(2-trifluoromethyl-phenylsulfanyl)-propyl]-morpholine(56C)

Compound 56C (Example 16C) was obtained from 55C (0.8 g, 1.95 mmol),solid supported Hünig's base (Argonaut, 3.56 mmol/g, 1.65 g, 5.85 mmol,3 eq) and α-chloroethyl chlorofonrate (0.4 ml, 3.9 mmol, 2 eq) inanhydrous dichloromethane (20 ml) following General Procedure 2Ca as acolourless oil (0.5 g, 85% yield). Chiral HPLC on a ChiralCel-OD(3671)column using 50% heptane in ethanol [v/v] gave 2 fractions (Rt=8.793 minand 10.443 min). Conversion into fumarate salt 56C was carried out bydissolving in diethyl ether and addition of small amount of methanol.Data for 56C derived from fraction with Rt=8.793 min: MW 435.46;C₁₉H₂₄F₃NO₅S; ¹H NMR (d₃-MeOD): 6.2-6.3 (2H, m), 6.1-6.2 (1H, m), 5.2(1H, s), 2.6-2.7 (2H, m), 2.2-2.4 (1H, m), 1.6-1.9 (4H, m), 1.6-1.7 (1H,m), −0.4-−0.5 (6H, m).

EXAMPLE 17C 2-[2-Methyl-1-(2-trifluoromethyl-phenoxy)-propyl]-morpholine(58C)4-Benzyl-2-[2-methyl-1-(2-trifluoromethyl-phenoxy)-propyl]-morpholine(57C)

To a solution of 53Ca (0.146 g, 0.585 mmol) in dry dimethylformamide (2ml) under nitrogen and ice-cooling was added sodium hydride (26 mg of a60% dispersion in oil, 0.644 mmol) portionwise. The reaction was allowedto warm to room temperature for 30 minutes before addition of2-fluoro-benzotriflouride (0.07 ml, 0.66 mmol). After stirring for 12hours, another 0.5 equivalents of reagents were added and the reactionmixture heated to 40° C. for 30 minutes and then to 60° C. for another 2hours. The crude reaction mixture was purified by ion-exchange columnchromatography followed by preparative HPLC to give 57C (0.208 g, 92%yield) MW 393.45; C₂₂H₂₆F₃NO₂; LCMS (6 min method): m/z 394 [M+H]⁺;RT=3.150.

2-[2-Methyl-1-(2-trifluoromethyl-phenoxy)-propyl]-morpholine (58C)

Compound 58C (Example 17C) was obtained from 57C (0.21 g, 0.53 mmol),solid supported Hünig's base (Argonaut, 3.56 mmol/g, 0.45 g, 1.5 mmol, 3eq) and α-chloroethyl chlorofornate (0.11 ml, 1.06 mmol, 2 eq) inanhydrous dichloromethane (10 ml) following General Procedure 2C as acolourless oil (0.147 g, 92% yield) MW 303.33; C₁₅H₂₀F₃NO₂; ¹H NMR(CDCl₃): 7.5-7.6 (1H, m), 7.2-7.4 (1H, m), 7.0-7.1 (1H, m), 6.8-6.95(1H, m), 4.15-4.25 (1H, m), 3.6-3.9 (2H, m), 3.4-3.6 (1H, m), 2.6-2.9(4H, m), 2.15 (1H, br, s)1.8-2.1 (1H, m), 1.1-1.2 (6H, m); LCMS (12 minmethod): m/z 304 [M+H]⁺; RT=4.862.

The following examples illustrate compounds of of Formulae (ID) aboveand methods for their preparation.

Scheme 1D—Preparation of Intermediates1-Phenyl-3,4-dihydro-1H-quinolin-2-one (2Da)

A stirred mixture of 3,4-Dihydro-1H-quinolin-2-one (1Da) (1.47 g. 10mmol), K₂CO₃ (2.9 g, 21 mmol), trans-cyclohexane-1,2-diamine (240 μL, 2mmol) and bromobenzene (3.16 mL, 30 mmol) in 1,4-dioxane (10 mL) washeated under a nitrogen atmosphere at 125° C. for 5 min to deoxygenatethe reaction mixture. Copper (I) iodide (380 mg, 2 mmol) was added inone portion and the reaction mixture was refluxed overnight at 125° C.After cooling to rt, the reaction mixture was poured into ethyl acetate(100 mL) and extracted with water. The organic layer was separated,dried over MgSO₄ and concentrated. Treatment of the residue with ether(100 mL) and cooling (ice bath) gave the product as a white solid afterfiltration (1.77 g, 79%).

6-Fluoro-1-p-tolyl-3,4-dihydro-1H-quinolin-2-one (2Db)

This was prepared using the method described for (2Da) using6-Fluoro-3,4-dihydro-1H-quinolin-2-one (1Db) (617 mg, 3.7 mmol) and4-bromotoluene (1.91 g, 11 mmol) to give the crude product, which waspurified using automated chromatography (silica) (0 to 60% ethylacetatecyclohexane gradient) to provide the product as a light brownsolid (880 mg, 92%).

3-Methyl-1-phenyl-3,4-dihydro-1H-quinolin-2-one (3Da)

To a soln of (2Da) (892 mg, 4 mmol) in anhydrous THF (40 mL) at −78° C.under nitrogen was added LiHMDS (4.4 mL, 1M soln in hexanes, 4.4 mmol)dropwise over 10 min. The reaction mixture was left at −78° C. for 30min and then a solution of methyl iodide (298 μL, 4.8 mmol) in THF (1mL) was added dropwise. The reaction mixture was warmed slowly to rt,quenched with water (2 mL) and extracted with ethyl acetate (100 mL).The organic layer was separated, dried over MgSO₄ and concentrated. Theresidue was purified by column chromatograpy (silica, gradient 100%hexane to ethyl acetatehexane 3:10) giving the product as an oil (667mg, 70%).

3-Ethyl-1-phenyl-3,4-dihydro-1H-quinolin-2-one (3Db)

This was prepared in a similar manner to (3Da) on a 1.5 mmol scale using1-iodoethane (125 μL, 1.1 eq.) as the alkylating agent. The crudeproduct (378 mg) was used directly in the next step.

3-(3-Chloro-propyl)-1-phenyl-3,4-dihydro-1H-quinolin-2-one (4Da)

To a soln of (2Da) (892 mg, 4 mmol) in anhydrous THF (40 mL) at −78° C.under nitrogen was added LiHMDS (4.4 mL, 1M soln in hexanes, 4.4 mmol)dropwise over 10 min. The reaction mixture was left at −78° C. for 30min and then a solution of 1-bromo-3-chloropropane (405 μL, 4.4 mmol) inTHF (1 mL) was added dropwise. The reaction mixture was warmed slowly tort, quenched with water (2 mL) and extracted with ethyl acetate (100mL). The organic layer was separated, dried over MgSO₄ and concentrated.The crude product (1.2 g) was used directly in the next step.

3-(3-Chloro-propyl)-6-fluoro-1-p-tolyl-3,4-dihydro-1H-quinolin-2-one(4Db)

This was prepared from (2Db) (300 mg, 1.17 mmol) using the methoddescribed for (4Da) using 1-bromo-3-chloropropane (140 μL, 1.4 mmol) asthe alkylating agent. The crude product (399 mg) was used directly inthe next step.

3-(2-Chloro-ethyl)-1-phenyl-3,4-dihydro-1H-quinolin-2-one (4Dc)

This was prepared from (2Da) (892 mg, 4.0 mmol) using the methoddescribed for (4Da) using 1-bromo-2-chloroethane (365 μL, 4.4 mmol) asthe alkylating agent. The crude product (1 g) was used directly in thenext step.

3-(3-Chloro-propyl)-3-methyl-1-phenyl-3,4-dihydro-1H-quinolin-2-one(5Da)

This was prepared from (3Da) (462 mg, 1.95 mmol) using the methoddescribed for (4Da) using 1-bromo-3-chloropropane (270 μL, 2.7 mmol) asthe alkylating agent. The crude product (650 mg) was used directly inthe next step.

3-(3-Chloro-propyl)-3-ethyl-1-phenyl-3,4-dihydro-1H-quinolin-2-one (5Db)

This was prepared from (3Db) (378 mg, 1.5 mmol) using the methoddescribed for (4Da) using 1-bromo-3-chloropropane (179 μL, 1.8 mmol) asthe alkylating agent. The crude product (528 mg) was used directly inthe next step.

Scheme 1D—Examples EXAMPLE 1D3-(3-Methylamino-propyl)-1-phenyl-3,4-dihydro-1H-quinolin-2-one (6Da)

A soln of (4Da) (1.2 g, 4 mmol), potassium iodide (200 mg, 1.2 mmol) andaqueous 40% methylamine (12 mL) in ethanol (30 mL) was refluxed at 100°C. under nitrogen for 3 h. The reaction mixture was cooled, poured intowater and extracted with ethyl acetate (100 mL). The organic layer wasseparated, dried over MgSO₄ and concentrated. The product was purifiedby preparative LCMS to give 500 mg of the racemate. The racemate wasseparated into its individual enantiomers using chiral HPLC. ¹H NMR (300MHz, CDCl₃) (racemate & isomer) δ 1.5-1.73 (m, 4H), 1.88-1.97 (m, 1H),2.43 (s, 3H), 2.62 (t, J=6.69 Hz, 2H), 2.70-2.79 (m, 1H), 2.84-2.92 (m,1H), 3.15 (dd, J=15.45, 5.28 Hz, 1H), 6.33 (d, J=7.73 Hz, 1H), 6.95-7.06(m, 2H), 7.19-7.22 (m, 3H), 7.38-7.43 (m, 1H), 7.47-7.52 (m, 2H). LCMS(12 minute method) [M+H]⁺=295@Rt 4.0 min (100%).

EXAMPLE 2D6-Fluoro-3-(3-methylamino-propyl)-1-p-tolyl-3,4-dihydro-1H-quinolin-2-one(6Db)

This was prepared in an identical manner to (6Da) using crude (4Db) (399mg) to give the crude product, which was purified by preparative LCMS togive the product (35 mg). ¹ H NMR (300 MHz, CDCl₃) (racemate) δ1.40-1.70 (m, 3H), 1.75-1.90 (m, 4H), 2.34 (s, 3H), 2.36 (s, 3H),2.50-2.83 (m, 2H), 3.01-3.08 (m, 1H), 6.21-6.26 (m, 1H), 6.62-6.68 (m,1H), 6.82-6.86 (m, 1H), 6.99 (d, J=8.1 Hz, 2H), 7.22 (d, J=8.1 Hz, 2H).LCMS (12 minute method) [M+H]⁺=327@ Rt 4.8 min (100%).

EXAMPLE 3D3-(2-Methylamino-ethyl)-1-phenyl-3,4-dihydro-1H-quinolin-2-one (6Dc)

This was prepared in an identical manner to (6Da) using crude (4Dc) (1g)to give the racemate (80 mg). The racemate was separated into itsindividual enantiomers using chiral HPLC. ¹H NMR (300 MHz, CDCl₃)(racemate & isomer) δ ppm 1.64-1.76 (m, 1H), 1.79 (br, 1H), 2.03-2.18(m, 1H), 2.44 (s, 3H), 2.71-2.82 (m, 2H), 2.82-2.94 (m, 2H), 3.09-3.21(m, 1H), 6.33 (dd, J=7.91, 1.32 Hz, 1H), 6.94-7.07 (m, 2H), 7.18-7.24(m, 3H), 7.37-7.44 (m, 1H), 7.47-7.54 (m, 2H). LCMS (12 minute method)[M+H]⁺=281@Rt 3.82 min (100%).

EXAMPLE 4D3-Methyl-3-(3-methylamino-propyl)-1-phenyl-3,4-dihydro-1H-quinolin-2-one(7Da)

This was prepared in an identical manner to (6Da) using crude (5Da) (650mg) to give the crude product (198 mg), which was purified bypreparative LCMS. The purified racemate was then separated into itsindividual enantiomers using chiral HPLC. ¹H NMR (300 MHz, CDCl₃)(isomer) δ ppm 1.27 (s, 3H), 1.43 (br, 1H), 1.53-1.66 (m, 4H), 2.39 (s,3H), 2.54 (t, J=6.12 Hz, 2H), 2.91 (d, J=15.64 Hz, 1H), 2.98 (d, J=15.64Hz, 1H), 6.28 (dd, J=7.91, 1.32 Hz, 1H), 6.97 (td, J=7.21, 1.41 Hz, 1H),7.03 (td, J=7.68, 1.98 Hz, 1H), 7.14-7.22 (m, 3H), 7.36-7.44 (m, 1H),7.46-7.53 (m, 2H). LCMS (12 minute method) [M+H]⁺=309@Rt 4.21 min(100%).

EXAMPLE 5D3-Ethyl-3-(3-methylamino-propyl)-1-phenyl-3,4-dihydro-1H-quinolin-2-one(7Db)

This was prepared in an identical manner to (6Da) using crude (5Db) (528mg) to give the crude product (105 mg), which was purified bypreparative LCMS. The purified racemate was then separated into itsindividual enantiomers using chiral HPLC. ¹H NMR (300 MHz, CDCl₃)(racemate) δ 0.93 (t, J=7.53 Hz, 3H), 1.56-1.75 (m, 6H), 1.91 (bs, 1H),2.41 (s, 3H), 2.55-2.60 (m, 2H), 2.91 (d, J=15.82, 1H), 3.02 (d,J=15.82, 1H), 6.25-6.28 (m, 1H), 6.94-7.05 (m, 2H), 7.16-7.19 (m, 3H),7.38-7.43 (m, 1H), 7.4-7.52 (m, 2H). ¹H NMR (300 MHz, MeOD-d4) (isomerD-tartrate salt) δ 0.85 (t, J=7.53 Hz, 3H), 1.45-1.75 (m, 6H), 2.57 (s,2H), 2.83-2.89 (m, 2H), 3.01-3.06 (d, J=16.01, 1H), 4.32 (s, 2H),6.11-6.14 (m, 1H), 6.89-6.97 (m, 2H), 7.09 (d, J=7.16 Hz, 2H), 7.15-7.18(m, 1H), 7.37 (t, J=7.35 Hz, 1H), 7.46 (t, J=7.35 Hz, 2H). LCMS (12minute method) [M+H]⁺=323@Rt 4.9 min (98%).

Scheme 2D—Preparation of Intermediates1-p-Tolyl-3,4-dihydro-1H-quinolin-2-one (2Dc)

A stirred mixture of 3,4-Dihydro-1H-quinolin-2-one (1Da) (4.41 g. 30mmol), K₂CO₃ (8.7 g, 63 mmol), trans-cyclohexane-1,2-diamine (720 μL, 2mmol) and 4-bromotoluene (15.4 g, 90 mmol) in 1,4-dioxane (30 mL) washeated under a nitrogen atmosphere at 125° C. for 5 min to deoxygenatethe reaction mixture. Copper (I) iodide (1.14 g, 2 mmol) was added inone portion and the reaction mixture was refluxed overnight at 125° C.After cooling to rt, the reaction mixture was filtered through celite,poured into ethyl acetate (100 mL) and extracted with water. The organiclayer was separated, dried over MgSO₄ and concentrated. Treatment of theresidue with ether (200 mL) and cooling (ice bath) gave the product as awhite solid after filtration (6.2 g, 87%).

1-Phenyl-3-propyl-3,4-dihydro-1H-quinolin-2-one (3Dc)

This was prepared from (2Da) (669 mg, 3 mmol) and 1-iodopropane (352 μl,1.2 eq.) as the alkylating agent. The crude product (780 mg) was useddirectly in the next step.

3-Ethyl-1-p-tolyl-3,4-dihydro-1H-quinolin-2-one (3Dd)

This was prepared from (2Dc) (711 mg, 3 mmol) and 1-iodoethane (265 μl,1.2 eq.) as the alkylating agent. The crude product (800 mg) was useddirectly in the next step.

3-Propyl-1-p-tolyl-3,4-dihydro-1H-quinolin-2-one (3De)

This was prepared from (2Dc) (711 mg, 3 mmol) and 1-iodopropane (352 μl,1.2 eq.) as the alkylating agent. The crude product (840 mg) was useddirectly in the next step.

3-Butyl-1-p-tolyl-3,4-dihydro-1H-quinolin-2-one (3Df)

This was prepared from (2Dc) (711 mg, 3 mmol) and 1-iodobutane (354 μl,1.1 eq.) as the alkylating agent. The crude product (790 mg) was useddirectly in the next step.

3-Isopropyl-1-p-tolyl-3,4-dihydro-1H-quinolin-2-one (3Dg)

This was prepared from (2Dc) (711 mg, 3 mmol) and 2-iodopropane (330 μl,1.1 eq.) as the alkylating agent. The crude product (806 mg) was useddirectly in the next step.

3-Allyl-3-ethyl-1-p-tolyl-3,4-dihydro-1H-quinolin-2-one (11Db)

To a soln of (3Dd) (800 mg, 2.7 mmol) in anhydrous THF (30 mL) at −78°C. under nitrogen was added LiHMDS (3 mL, 1M soln in hexanes, 3 mmol)dropwise over 10 min. The reaction mixture was left at −78° C. for 30min and then a solution of allyl bromide (280 μL, 3.2 mmol) in THF (1mL) was added dropwise. The reaction mixture was warmed slowly to rt,quenched with water (2 mL) and extracted with ethyl acetate (100 mL).The organic layer was separated, dried over MgSO₄ and concentrated. Thecrude product (920 mg) was used directly in the next step.

3-Ethyl-3-(3-hydroxypropyl)-1-p-tolyl-3,4-dihydro-1H-quinolin-2-one(12Db)

To a soln of (11Db) (732 mg, 2.4 mmol) in anhydrous THF (25 mL) at 0° C.under nitrogen was added 9-BBN (12 mL, 0.5M soln in THF, 6 mmol, 2.5eq.) dropwise over 10 min. The reaction mixture was warmed to rt andleft to stir overnight. The resultant yellow soln was cooled to 0° C.and then quenched carefully with ethanol (3 mL), followed by aq. NaOH(1.8 mL, 3N soln). Finally, aq. H₂O₂ (1.8 mL, 37% soln) was addeddropwise maintaining the internal reaction mixture temp between 5 and10° C. The reaction mixture was warmed to rt and then refluxed for 90min. The reaction mixture was cooled to rt, poured into ethyl acetateand water and extracted. The organic layer was separated, dried overMgSO₄ and concentrated. The crude product was purified using automatedchromatography (silica) (0 to 60% ethyl acetatecyclohexane gradient) toprovide (12Db) as a clear oil (540 mg, 70%).

Scheme 2D—Examples EXAMPLE 6D3-Ethyl-3-(3-methylamino-propyl)-1-p-tolyl-3,4-dihydro-1H-quinolin-2-one(13Db)

To a soln of (12Db) (540 mg, 1.67 mmol) and triethylamine (350 μL, 2.5mmol) in anhydrous THF (20 mL) at 0° C. under nitrogen was addeddropwise a soln of methanesulfonyl chloride (142 μL, 1.8 mmol) in THF (1mL). The reaction mixture was warmed to rt and stirred for 3 h. Thereaction mixture was poured into ethyl acetate and water and extracted.The organic layer was separated, dried over MgSO₄ and concentrated. Thecrude mesylate (670 mg, 100%) was dissolved in ethanol (10 mL) andaqueous 40% methylamine (5 mL) and heated at 65° C. under nitrogen for 2h. The reaction mixture was cooled, poured into water and extracted withethyl acetate (100 mL). The organic layer was separated, dried overMgSO₄ and concentrated. The product was purified by SCX-2 to give 384 mgof the racemate. The racemate was separated into its individualenantiomers using chiral HPLC. Each enantiomer was dissolved in CH₂Cl₂(2 mL) and treated with 1 equivalent of D-tartaric acid dissolved in aminimum volume of warm methanol. The resultant soln was concentrated andthe solid was dried under vacuo to provide the D-tartrate salt of theamine. ¹H NMR (300 MHz, CDCl₃) (racemate) δ 0.92 (t, J=7.44 Hz, 3H),1.49-1.75 (m, 6H), 1.81 (br, 1H), 2.40 (s, 6H), 2.57 (t, J=6.59 Hz, 2H),2.89 (d, J=15.82 Hz, 1H), 3.00 (d, J=15.82 Hz, 1H), 6.29 (d, J=7.91 Hz,1H), 6.92-7.08 (m, 4H), 7.16 (d, J=7.16 Hz, 1H), 7.29 (d, J=7.91 Hz,2H). ¹H NMR (300 MHz, MeOD-d4) (isomer D-tartrate salt) δ 0.93 (t,J=7.44 Hz, 3H), 1.54-1.84 (m, 6H), 2.42 (s, 3H), 2.66 (s, 3H), 2.91-3.00(m, 3H), 3.11 (d, J=15.83 Hz, 1H), 4.41 (s, 2H), 6.22-6.27 (m, 1H),6.80-7.07 (m, 4H), 7.21-7.27 (m, 1H), 7.36 (d, J=7.91 Hz, 2H). LCMS (12minute method) [M+H]⁺=337@Rt 5.21 min (100%).

EXAMPLE 7D3-(3-Methylamino-propyl)-1-phenyl-3-propyl-3,4-dihydro-1H-quinolin-2-one(13Da)

This was prepared from (3Dc) (780 mg, 2.9 mmol) using the same syntheticsequence described above (3Dd to 13Db) to give 233 mg of the racemate.The racemate was separated into its individual enantiomers using chiralHPLC and each enantiomer was converted into its D-tartrate salt asdescribed for (13Db). ¹H NMR (300 MHz, CDCl₃) (racemate) δ 0.88 (t,J=7.16 Hz, 3H), 1.26-1.48 (m, 2H), 1.50-1.78 (m, 7H), 2.40 (s, 3H), 2.56(t, J=6.59 Hz, 2H), 2.92 (d, J=15.83 Hz, 1H), 3.01 (d, J=15.83 Hz, 1H),6.25-6.28 (m, 1H), 6.94-7.05 (m, 2H), 7.16-7.19 (m, 3H), 7.37-7.42 (m,1H), 7.47-7.52 (m, 2H). ¹H NMR (300 MHz, MeOD-d4) (isomer D-tartratesalt) δ 0.77-0.82 (t, J=7.06 Hz, 3H), 1.24-1.35 (m, 2H), 1.44-1.51 (m,2H), 1.69 (bs, 3H), 2.56 (s, 3H), 2.84-2.89 (m, 3H), 3.01-3.06 (d,J=15.83 Hz, 1H), 3.20-3.22 (q, J=1.55 Hz, 2H), 4.30 (s, 2H), 6.11-6.14(dd, J=7.72, 2.26 Hz, 1H), 6.89-6.97 (m, 2H), 7.07-7.10 (m, 2H),7.14-7.17 (m, 1H), 7.34-7.39 (t, J=7.35 Hz, 1H), 7.43-7.48 (t, J=7.35Hz, 2H). LCMS (12 minute method) [M+H]⁺=337@Rt 5.2 min (100%).

EXAMPLE 8D3-(3-Methylamino-propyl)-3-propyl-1-D-tolyl-3,4-dihydro-1H-quinolin-2-one(13Dc)

This was prepared from (3De) (840 mg, 2.6 mmol) using the same syntheticsequence described above (3Dd to 13Db) to give 393 mg of the racemate.The racemate was separated into its individual enantiomers using chiralHPLC and each enantiomer was converted into its D-tartrate salt asdescribed for (13Db). ¹H NMR (300 MHz, CDCl₃) (racemate) δ 0.88 (t,J=7.16 Hz, 3H), 1.20-1.75 (m, 11H), 2.39 (s, 3H), 2.40 (s, 3H), 2.90 (d,J=15.64 Hz, 1H), 2.99 (d, J=15.64 Hz, 1H), 6.29 (d, J=7.72 Hz, 1H),6.93-7.07 (m, 4H), 7.14-7.16 (m, 1H), 7.25-7.31 (m, 2H). ¹H NMR (300MHz, MeOD-d4) (isomer D-tartrate salt) δ 0.91 (t, J=7.06 Hz, 3H),1.28-1.85 (m, 8H), 2.44 (s, 3H), 2.68 (s, 3H), 2.94-2.99 (m, 3H), 3.14(d, J=15.82 Hz, 1H), 4.41 (s, 2H), 6.25-6.28 (m, 1H), 7.02-7.07 (m, 4H),7.25-7.28 (m, 1H), 7.38 (d, J=7.91 Hz, 2H). LCMS (12 minute method)[M+H]⁺=351@Rt 5.6 min (100%).

EXAMPLE 9D3-Butyl-3-(3-methylamino-propyl)-1-p-tolyl-3,4-dihydro-1H-quinolin-2-one(13Dd)

This was prepared from (3Df) (790 mg, 2.7 mmol) using the same syntheticsequence described above (3Dd to 13Db) to give 334 mg of the racemate.The racemate was separated into its individual enantiomers using chiralHPLC and each enantiomer was converted into its D-tartrate salt asdescribed for (13Db). ¹H NMR (300 MHz, CDCl₃) (racemate) δ 0.87 (t,J=6.97 Hz, 3H), 1.20-1.40 (m, 4H), 1.55-1.74 (m, 6H), 2.40 (s, 3H), 2.40(s, 3H), 2.55 (t, J=6.78 Hz, 3H), 2.91 (d, J=15.63 Hz, 1H), 2.99 (d,J=15.63 Hz, 1H), 6.28-6.31 (m, 1H), 6.93-7.00 (m, 2H), 7.02-7.06 (m,2H), 7.14-7.16 (m, 1H), 7.29 (d, J=8.07 Hz, 2H). ¹H NMR (300 MHz,MeOD-d4) (isomer D-tartrate salt) δ 0.90 (t, J=6.97 Hz, 3H), 1.20-1.85(m, 10H), 2.44 (s, 3H), 2.68 (s, 3H), 2.94-2.99 (m, 3H), 3.14 (d,J=15.82 Hz, 1H), 4.42 (s, 2H), 6.25-6.28 (m, 1H), 7.00-7.07 (m, 4H),7.25-7.28 (m, 1H), 7.38 (d, J=7.91 Hz, 2H). LCMS (12 minute method)[M+H]⁺=365@Rt 5.9 min (100%).

EXAMPLE 10D3-Isopropyl-3-(3-methylamino-propyl)-1-p-tolyl-3,4-dihydro-1H-quinolin-2-one(13De)

This was prepared from (3Dg) (806 mg, 2.89 mmol) using the samesynthetic sequence described above (3Dd to 13Db) to give 307 mg of theracemate. ¹H NMR (300 MHz, CDCl₃) (racemate) δ ppm 0.92 (dd, J=8.95,6.88 Hz, 6H), 1.39-1.88 (m, 5H), 2.12-2.23 (m, 1H), 2.39 (s, 3H), 2.40(s, 3H), 2.56 (t, J=6.78 Hz, 2H), 2.94 (d, J=15.92 Hz, 1H), 3.00 (d,J=15.92 Hz, 1H), 6.28 (dd, J=7.82, 1.04 Hz, 1H), 6.92-7.06 (m, 4H), 7.16(dd, J=6.97, 1.13 Hz, 1H), 7.29 (d, J3 7.91 Hz, 2H). LCMS (12 minutemethod) [M+H]⁺=351@Rt 5.55 min (100%).

EXAMPLE 11D6-Chloro-3-ethyl-3-(3-methylamino-propyl)-1-p-tolyl-3,4-dihydro-1H-quinolin-2-one(13Df)

This was prepared from (1Dc) using the same synthetic sequence describedabove to give 205 mg of the racemate. The racemate was separated intoits individual enantiomers using chiral HPLC and each enantiomer wasconverted into its D-tartrate salt as described for (13Db). ¹H NMR (300MHz, CDCl₃) (racemate) δ ppm 0.91 (t, J=7.44 Hz, 3H), 1.50-1.75 (m, 6H),2.15 (br, 1H), 2.40 (s, 3H), 2.41 (s, 3H), 2.55-2.64 (m, 2H), 2.85 (d,J=16.01 Hz, 1H), 2.97 (d, J=16.01 Hz, 1H), 6.23 (d, J=8.85 Hz, 1H), 6.97(dd, J=8.67, 2.45 Hz, 1H), 7.02 (d, J=8.29 Hz, 2H), 7.14 (d, J=2.26 Hz,1H), 7.29 (d, J=8.10 Hz, 2H). ¹H NMR (300 MHz, MeOD-d4) (isomer,D-tartrate salt) δ ppm 0.84 (t, J=7.35 Hz, 3H), 1.40-1.75 (m, 6H), 2.32(s, 3H), 2.57 (s, 3H), 2.80-2.92 (m, 3H), 3.01 (d, J=16.20 Hz, 1H), 4.31(s, 2H), 6.13 (d, J=8.67 Hz, 1H), 6.92-6.98 (m, 3H), 7.19 (d, J=2.26 Hz,1H), 7.26 (d, J=7.91 Hz, 2H). LCMS (12 minute method) [M+H]⁺=371/373 @Rt5.75 min (100%).

EXAMPLE 12D6-Chloro-1-(4-chloro-phenyl)-3-ethyl-3-(3-methylamino-propyl)-3,4-dihydro-1H-quinolin-2-one(13Dg)

This was prepared from (1Dc) using the same synthetic sequence describedabove to give 222 mg of the racemate, which was purified by preparativeLCMS. ¹H NMR (300 MHz, CDCl₃) (racemate) δ ppm 0.84 (t, J=7.44 Hz, 3H),1.40-1.70 (m, 6H), 2.35 (br, 4H), 2.49-2.56 (m, 2H), 2.80 (d, J=16.01Hz, 1H), 2.90 (d, J=16.01 Hz, 1H), 6.14 (d, J=8.67 Hz, 1H), 6.93 (dd,J=8.67, 2.26 Hz, 1H), 7.04 (ddd, J=9.04, 2.83, 2.45 Hz, 2H), 7.09 (d,J=2.26 Hz, 1H), 7.36-7.43 (m, 2H). LCMS (12 minute method)[M+H]⁺=391/393 @Rt 5.67 min (92%).

Scheme 3D—Preparation of Intermediates

1-(4-Methoxy-benzyl)-3,4-dihydro-1H-quinolin-2-one (14D)

A 5 litre flange-neck flask equipped with an air stirrer and paddle,thermometer, nitrogen bubbler and pressure equalising dropping funnelwas charged with sodium hydride (25.5 g, 60% oil dispersion, 0.637 mol)and 40-60 pet. ether (100 ml). The mixture was stirred briefly and thenallowed to settle under nitrogen. After decanting the supernatantliquid, the vessel was charged with dimethylformamide (2 litres). Thewell stirred suspension was cooled to 7-8° C. using an externalice-bath. Then a soln of 3,4-dihydro-1H-quinolin-2-one (1a) (73.6 g, 0.5mole) in anhydrous dimethylformamide (500 ml) was added dropwise over 25min. The mixture was stirred at 7-8° C. for 30 min. then 4-methoxybenzylchloride (102 g, 0.65 mole, 1.3 eq.) was added over 10 min. The reactionmixture was left to stir for 2 h. at <10° C. then allowed to warm-up toroom temperature and stirred overnight. The stirred reaction mixture wasquenched with ice/water (2.5 litres) and cooled to 15° C. using anexternal ice-bath. The white solid was isolated by filtration and washedwith water. After drying in vacuo at 40° C. overnight the product wasobtained (113.4 g, 85%).

1-(4-Methoxy-benzyl)-3-methyl-3,4-dihydro-1H-quinolin-2-one (15D)

To a soln of (14) (20 g, 75 mmol) in anhydrous THF (400 mL) at −78° C.under nitrogen was added LiHMDS (78.6 mL, 1M soln in hexanes, 78.6 mmol)dropwise over 10 min. The reaction mixture was left at −78° C. for 30min and then a solution of methyl iodide (5.13 mL, 83 mmol) in THF (5mL) was added dropwise. The reaction mixture was warmed slowly to rt,quenched with water (50 mL) and extracted with ethyl acetate (400 mL).The organic layer was separated, dried over MgSO₄ and concentrated togive the product as a yellow solid (21 g, 100%) that was used directlyin the next step.

3-Allyl-1-(4-methoxy-benzyl)-3-methyl-3,4-dihydro-1H-quinolin-2-one(16Db)

To a soln of (15D) (20.5 g, 73 mmol) in anhydrous THF (400 mL) at −78°C. under nitrogen was added LiHMDS (80 mL, 1M soln in hexanes, 80 mmol)dropwise over 10 min. The reaction mixture was left at −78° C. for 30min and then a solution of allyl bromide (7.6 mL, 87 mmol) in THF (5 mL)was added dropwise. The reaction mixture was warmed slowly to rt,quenched with water (100 mL) and extracted with ethyl acetate (400 mL).The organic layer was separated, dried over MgSO₄ and concentrated togive the product as an orange oil (23.9 g, 100%) that was used directlyin the next step.

3-(3-Hydroxy-propyl)-1-(4-methoxy-benzyl)-3-methyl-3,4,4a,8a-tetrahydro-1H-quinolin-2-one(17Db)

To a soln of (16Db) (23.9 g, 74 mmol) in anhydrous THF (400 mL) at 0° C.under nitrogen was added 9-BBN (370 mL, 0.5M soln in THF, 185 mmol, 2.5eq.) dropwise over 10 min. The reaction mixture was warmed to rt andleft to stir overnight. The resultant yellow soln was cooled to 0° C.and then quenched carefully with ethanol (95 mL), followed by aq. NaOH(60 mL, 3N soln). Finally, aq. H₂O₂ (60 mL, 37% soln) was added dropwisemaintaining the internal reaction mixture temp between 5 and 10° C. Thereaction mixture was warmed to rt and then refluxed for 90 min. Thereaction mixture was cooled to rt, poured into ethyl acetate and waterand extracted. The organic layer was separated, dried over MgSO₄ andconcentrated. The crude product was purified using automatedchromatography (silica) (0 to 80% ethyl acetatecyclohexane gradient) toprovide the product as a clear oil (21.3 g, 84%).

1-(4-Methoxy-benzyl)-3-methyl-3-(3-methylamino-propyl)-3,4,4a,8a-tetrahydro-1H-quinolin-2-one(18Db)

To a soln of (17Db) (18 g, 53 mmol) and triethylamine (11.1 mL, 79 mmol)in anhydrous THF (450 mL) at 0° C. under nitrogen was added dropwise asoln of methanesulfonyl chloride (4.52 mL, 58 mmol) in THF (50 mL). Thereaction mixture was warmed to rt and stirred for 3 h. The reactionmixture was poured into ethyl acetate and water and extracted. Theorganic layer was separated, dried over MgSO₄ and concentrated. Thecrude mesylate (22 g, 99%) was dissolved in ethanol (500 mL) and aqueous40% methylamine (200 mL) and heated at 65° C. under nitrogen for 2 h.The reaction mixture was cooled, concentrated and then extracted withethyl acetate (300 mL). The organic layer was washed with water, brine,dried over MgSO₄ and concentrated to give the crude product (17.8 g,96%).

Methyl-[3-(3-methyl-2-oxo-1,2,3,4,4a,8a-hexahydro-quinolin-3-yl)-propyl]-carbamicacid tert-butyl ester (19Db)

A mixture of (18Db) (17.8 g, 50.5 mmol) and anisole (5.5 mL, 50.5 mmol)in trifluoroacetic acid (250 mL) was heated at 65° C. under nitrogen for2 h. The reaction mixture was concentrated under vacuo and the residuewas dissolved in methanol (10 mL). The methanol soln was applied to anSCX-2 column (300 g, pre-washed with methanol) and the column washedwith methanol (approx 1 litre) until the soln became colourless. Theproduct was eluted with 2N NH₃ in methanol (500 mL) and the basic solnwas concentrated to provide3-Methyl-3-(3-methylamino-propyl)-3,4-dihydro-1H-quinolin-2-one (9 g,77%). To a soln of this amine (8.6 g, 37 mmol) in anhydrous THF (350 mL)at 0° C. was added a soln of di-tert-butyl dicarbonate (8.34 g, 97%,50.5 mmol) in THF (20 mL) dropwise. The reaction mixture was warmed tort and stirred for 3 h. The reaction mixture was poured into ethylacetate (400 mL) and water (200 mL) and extracted. The organic layer wasseparated, dried over MgSO₄ and concentrated to give the product as ayellow solid (12.26 g, 100%). This material was used without furtherpurification.

Methyl-[3-(2-oxo-1,2,3,4-tetrahydro-quinolin-3-yl)-propyl]-carbamic acidtert-butyl ester (19Da)

This was prepared from (14D) using the same synthetic sequence describedabove.

[3-(6-Chloro-1,2,3,4-tetrahydro-quinolin-3-yl)-propyl]-methyl-carbamicacid tert-butyl ester (20Da)

To a soln of (19Da) (2.75 g, 8.6 mmol) in anhydrous DMF (25 mL) at 0° C.was added dropwise a soln of N-chlorosuccinimide (1.17 g, 8.7 mmol) inanhydrous DMF (3 mL). The reaction mixture was warmed to rt, stirredovernight and then poured into ethyl acetate (100 mL) and water (50 mL)and extracted. The organic layer was separated, dried over MgSO₄ andconcentrated to provide the product as a yellow oil 3 g, 98%) that wasused without further purification.

Scheme 3D EXAMPLES EXAMPLE 13D3-(3-Methylamino-propyl)-1-p-tolyl-3,4-dihydro-1H-quinolin-2-one (21Da)

A stirred mixture of (19Da) (100 mg. 0.31 mmol), K₂CO₃ (92 mg, 0.66mmol), trans-cyclohexane-1,2-diamine (8 μL, 0.06 mmol) and4-bromotoluene (162 mg, 0.94 mmol) in 1,4-dioxane (0.5 mL) was heatedunder a nitrogen atmosphere at 125° C. for 5 min to deoxygenate thereaction mixture. Copper (I) iodide (12 mg, 0.06 mmol) was added in oneportion and the reaction mixture was refluxed overnight at 125° C. Aftercooling to rt, the reaction mixture was poured into ethyl acetate (100mL) and extracted with water. The organic layer was separated, driedover MgSO₄ and concentrated. The crude product was purified usingautomated chromatography (silica) (0 to 80% ethyl acetate\cyclohexanegradient) to provide the Boc protected product (70 mg, 54%). To a solnof this material (70 mg, 0.17 mol) in DCM (2 mL), was addedtrifluoroacetic acid (197 μL, 2.55 mmol, 15 eq.). The reaction mixturewas left to stir at room temperature for 90 min, concentrated undervacuo poured into ethyl acetate (50 mL) and aq. NaHCO₃ (20 mL) andextracted. The organic layer was separated, dried over MgSO₄,concentrated and the crude product was purified by SCX-2 to provide theracemate (40 mg, 75%). The racemate was separated into its individualenantiomers using chiral HPLC. ¹H NMR (300 MHz, CDCl₃) (racemate) δ1.49-1.77 (m, 3H), 1.86-1.96 (m, 1H), 2.34 (bs, 1H), 2.40 (s, 3H), 2.43(s, 3H), 2.61-2.66 (t, J=6.88 Hz, 2H), 2.68-2.78 (m, 1H), 2.83-2.90 (m,1H), 3.09-3.17 (m, 1H), 6.36 (dd, J=7.7 Hz, 1.0 Hz, 1H), 6.94-7.03 (m,2H), 7.08 (d, J=8.2 Hz, 2H), 7.13-7.17 (m, 1H), 7.29 (d, J=8.1 Hz, 2H);¹H NMR (300 MHz, MeOD-d4) (isomer, D-tartrate salt) δ 1.64 (bs, 1H),1.89 (bs, 3H), 2.41(s, 3H), 2.70 (s, 3H), 2.75-2.87 (m, 1H), 2.91-3.06(m, 3H), 3.20 (dd, J=5.9, 15.26 Hz, 1H), 4.45 (s, 2H), 6.32-6.35 (m,1H), 7.00-7.12 (m, 4H), 7.28-7.30 (m, 1H), 7.37 (d, J=8.1 Hz, 2H). LCMS(12 minute method) [M+H]⁺=309 @ Rt 4.7 min (100%).

EXAMPLE 14D6-Chloro-3-(3-methylamino-propyl)-1-p-tolyl-3,4-dihydro-1H-quinolin-2-one(21Dn)

This was prepared from (20Da) (132 mg, 0.29 mmol) using the same methodsdescribed for (21Da) to provide the racemate (86 mg). ¹H NMR (300 MHz,CDCl₃) (racemate & isomer) δ 1.50-1.57 (m, 1H), 1.62-1.90 (m, 3H), 2.34(s, 3H), 2.41 (s, 3H), 2.63-2.82 (m, 5H), 3.00-3.07 (m, 1H), 6.22 (d,J=8.6 Hz, 1H), 6.92 (dd, J=2.45, 8.66 Hz, 1H 6.99 (d, J=8.1 Hz, 2H),7.11 (d, J=2.25 Hz, 1H), 7.23 (d, J=8.1 Hz, 2H). LCMS (12 minute method)[M+H]⁺=343/345 @ Rt 5.2 min (96%).

EXAMPLE 15D1-(3-Fluorophenyl)-3-(3-methylamino-propyl)-3,4-dihydro-1H-quinolin-2-one(21Db)

This was prepared from (19Da) (200 mg, 0.63 mmol) using the sametwo-step procedure described for (21Da) to provide the racemate (83 mg).¹H NMR (300 MHz, CDCl₃) (racemate) δ 1.60-1.70 (m, 1H), 1.92 (br, 3H),2.64 (bs, 3H), 2.72-2.74 (m, 1H), 2.86-3.09 (m, 4H), 6.35 (dd, J=7.72,1.510 Hz, 1H), 6.94-7.23 (m, 6H), 7.43-7.51 (m, 1H). LCMS (12 minutemethod) [M+H]⁺=313 @ Rt 4.4 min (100%).

EXAMPLE 16D1-(4-Chlorophenyl)-3-(3-methylamino-propyl)-3,4-dihydro-1H-quinolin-2-one(21Dc)

This was prepared from (19Da) (122 mg, 0.38 mmol) using the sametwo-step procedure described for (21Da) to provide the crude product,which was purified by SCX-2 to give the racemate (70 mg). ¹H NMR (300MHz, CDCl₃) (racemate) δ 1.49-1.73 (m, 3H), 1.89 (m, 2H), 2.43 (s, 3H),2.62 (t, J=6.79, 7.15 Hz, 2H), 2.68-2.78 (m, 1H), 2.83-2.93 (m, 1H),3.14 (dd, J=15.43, 5.37 Hz, 1H), 6.34 (dd, J=7.73, 1.14 Hz, 1H),6.96-7.09 (m, 2H), 7.14-7.21 (m, 3H), 7.45-7.48 (m, 2H). LCMS (12 minutemethod) [M+H]⁺=329/331 @ Rt 5.1 min (90%).

EXAMPLE 17D1-(3,4-Dichlorophenyl)-3-(3-methylamino-propyl)-3,4-dihydro-1H-quinolin-2-one(21Dd)

This was prepared from (19Da) (150 mg, 0.47 mmol) using the sametwo-step procedure described for (21Da) to provide the crude product,which was purified by SCX-2 to give the racemate (111 mg). ¹H NMR (300MHz, CDCl₃) (racemate) δ 1.49-1.75 (m, 3H), 1.83 (bs, 1H), 1.85-1.97 (m,1H), 2.43 (s, 3H), 2.63 (t, J=13.56, 6.59 Hz, 2H), 2.68-2.77 (m, 1H),2.83-2.94 (m, 1H), 3.13 (dd, J=15.45, 5.28 Hz, 1H), 6.36 (dd, J=7.73,0.93 Hz, 1H), 6.99-7.11 (m, 3H), 7.20-7.21 (m, 1H), 7.35 (d, J=2.26 Hz,1H), 7.57 (d, J=8.48 Hz, 1H). LCMS (12 minute method) [M+H]⁺=363/365 @Rt5.4 min (92%).

EXAMPLE 18D1-(3-Chlorophenyl)-3-(3-methylamino-propyl)-3,4-dihydro-1H-quinolin-2-one(21De)

This was prepared from (19Da) (200 mg, 0.63 mmol) using the sametwo-step procedure described for (21Da) to provide the crude product,which was purified by SCX-2 to give the racemate (138 mg). ¹H NMR (300MHz, CDCl₃) (racemate) δ 1.50-1.77 (m, 3H), 1.89-1.96 (m, 2H), 2.44 (s,3H), 2.64 (t, J=6.89 Hz, 2H), 2.69-2.78 (m, 1H), 2.84-2.93 (m, 1H,),3.10-3.17 (m, 1H), 6.33-6.36 (m, 1H), 6.97-7.10 (m, 2H), 7.11-7.15 (m,1H), 7.21-7.24 (m, 2H), 7.37-7.47 (m, 2H). LCMS (12 minute method)[M+H]⁺=329/331 @ Rt 5.01 min (90%).

EXAMPLE 19D1-(4-Fluorophenyl)-3-(3-methylamino-propyl)-3,4-dihydro-1H-quinolin-2-one(21Df)

This was prepared from (19Da) (200 mg, 0.63 mmol) using the sametwo-step procedure described for (21Da) to provide the crude product,which was purified by SCX-2 to give the racemate (48 mg). ¹H NMR (300MHz, CDCl₃) (racemate) δ 1.26-1.28 (m, 1H), 1.92 (m, 2H), 2.63 (bs, 1H),2.72 (m, 1H), 2.85-3.08 (m, 2H), 3.48-3.51 (m, 5H), 6.32-6.34 (d, J=7.91Hz, 1H), 7.01-7.70 (m, 2H), 7.16-7.19 (d, J=7.16 Hz, 5H), 9.46 (bs, 1H).LCMS (12 minute method) [M+H]⁺=313 @ Rt 4.5 min (100%).

EXAMPLE 20D1-(4-Ethylphenyl)-3-(3-methylamino-propyl)-3,4-dihydro-1H-quinolin-2-one(21Dg)

This was prepared from (19Da) (148 mg, 0.46 mmol) using the sametwo-step procedure described for (21Da) to provide the racemate (61 mg).¹H NMR (300 MHz, CDCl₃) (racemate) δ 1.25-1.30 (m, 1H), 1.52-1.67(m,1H), 1.69-1.80 (m, 2H), 1.87-1.98 (m, 1H), 2.46 (s, 3H), 2.67-2.92 (m,9H), 3.11-3.16 (m, 1H), 6.34-6.37 (m, 1H), 6.94-7.06 (m, 2H), 7.09-7.11(d, J=8.1 Hz, 2H), 7.17-7.20 (d, J=7.35 Hz, 1H), 7.30-7.33 (d, J=8.28Hz, 2H). LCMS (12 minute method) [M+H]⁺=323 @ Rt 5.4 min (98%).

EXAMPLE 21D3-Methyl-3-(3-methylamino-propyl)-1-p-tolyl-3,4-dihydro-1H-quinolin-2-one(21Dh)

This was prepared from (19Db) (806 mg, 2.89 mmol) using the same methodsdescribed for (21Da) to provide the racemate. The racemate was separatedinto its individual enantiomers using chiral HPLC. ¹H NMR (300 MHz,CDCl₃) (racemate & isomer) δ 1.24 (s, 3H), 1.60-1.65 (m, 4H), 2.40 (s,3H), 2.43 (s, 3H), 2.60-2.65 (m, 2H), 2.87 (d, J=15.73 Hz, 1H), 2.98 (d,J=15.73 Hz, 1H), 3.46 (br, 1H), 6.30 (dd, J=7.91, 1.13 Hz, 1H),6.90-7.05 (m, 2H), 7.05 (d, J=8.29 Hz, 2H), 7.10-7.20 (m, 1H), 7.29 (d,J=7.91 Hz, 2H). LCMS (12 minute method) [M+H]⁺=323 @Rt 5.06 min (100%).

EXAMPLE 22D1-(4-Chlorophenyl)-3-methyl-3-(3-methylamino-propyl)-3,4-dihydro-1H-quinolin-2-one(21Di)

This was prepared from (19Db) (100 mg, 0.30 mmol) using the same methodsdescribed for (21Da) to provide the racemate (97 mg). 1H NMR (300 MHz,CDCl₃) (racemate) δ ppm 1.25 (s, 3H), 1.55-1.65 (m, 4H), 2.41 (s, 3H),2.58 (m, 2H), 2.89 (d, J=15.82 Hz, 1H), 2.98 (d, J=15.82 Hz, 1H), 3.12(br, 1H), 6.29 (dd, J=7.91, 0.94 Hz, 1H), 6.95-7.10 (m, 2H), 7.14 (d,J=8.67 Hz, 2H), 7.15 (m, 1H), 7.45 (d, J=8.67 Hz, 2H). LCMS (12 minutemethod) [M+H]⁺=343/345 @Rt 5.09 min (100%).

EXAMPLE 23D1-(3,4-Difluorophenyl)-3-methyl-3-(3-methylamino-propyl)-3,4-dihydro-1H-quinolin-2-one(21Dj)

This was prepared from (19Db) (100 mg, 0.30 mmol) using the sametwo-step procedure described for (21Da) to provide the crude product,which was purified by SCX-2 to give the racemate (100 mg). ¹H NMR (300MHz, CDCl₃) (racemate) δ ppm 1.25 (s, 3H), 1.55-1.65 (m, 4H), 2.41 (s,3H), 2.50-2.60 (m, 2H), 2.89 (d, J=15.45 Hz, 1H), 2.90 (s, 1H), 2.98 (d,J=15.45 Hz, 1H), 6.30 (dd, J=7.91, 1.13 Hz, 1H), 6.90-7.10 (m, 4H), 7.18(dd, J=7.16, 1.32 Hz, 1H), 7.22-7.35 (m, 1H). LCMS (12 minute method)[M+H]⁺=345 @Rt 4.85 min (97%).

EXAMPLE 24D3-Methyl-3-(3-methylamino-propyl)-1-m-tolyl-3,4-dihydro-1H-quinolin-2-one(21Dk)

This was prepared from (19Db) (100 mg, 0.30 mmol) using the sametwo-step procedure described for (21Da) to provide the crude product,which was purified by SCX-2 to give the racemate (90 mg). ¹H NMR (300MHz, CDCl₃) (racemate) δ ppm 1.26 (s, 3H), 1.50-1.70 (m, 4H), 1.75 (s,1H), 2.38 (s, 3H), 2.39 (s, 3H), 2.50-2.60 (m, 2H), 2.89 (d, J=15.64 Hz,1H), 2.98 (d, J=15.64 Hz, 1H), 6.30 (dd, J=7.82, 1.04 Hz, 1H), 6.90-7.07(m, 4H), 7.18 (dd, J=13.66, 7.63 Hz, 2H), 7.37 (t, J=7.63 Hz, 1H). LCMS(12 minute method) [M+H]⁺=323 @Rt 5.09 min (98%).

EXAMPLE 25D1-(3,5-Difluorophenyl)-3-methyl-3-(3-methylamino-propyl)-3,4-dihydro-1H-quinolin-2-one(21Dl)

This was prepared from (19Db) (100 mg, 0.30 mmol) using the sametwo-step procedure described for (21Da) to provide the crude product,which was purified by SCX-2 to give the racemate (95 mg). ¹H NMR (300MHz, CDCl₃) (racemate) δ ppm 1.26 (s, 3H), 1.50-1.65 (m, 4H), 2.40 (s,3H), 2.50-2.60 (m, 2H), 2.82 (br, 1H), 2.89 (d, J=15.82 Hz, 1H), 2.97(d, J=15.82 Hz, 1H), 6.34 (dd, J=8.01, 1.04 Hz, 1H), 6.74-6.83 (m, 2H),6.83-6.92 (m, 1H), 6.97-7.13 (m, 2H), 7.19 (dd, J=7.06, 1.22 Hz, 1H).LCMS (12 minute method) [M+H]⁺=345 @ Rt 4.87 min, (97%).

EXAMPLE 26D6-Chloro-3-(3-methylamino-propyl)-1-phenyl-3,4-dihydro-1H-quinolin-2-one(21Dm)

This was prepared from (20Da) (285 mg, 0.8 mmol) using the same two-stepprocedure described for (21Da) to provide the crude product, which waspurified by preparative LCMS to give the racemate (62 mg). ¹H NMR (300MHz, CDCl₃) (racemate) δ 1.49-1.76 (m, 3H), 1.86-1.95 (m, 1H), 2.33 (bs,1H), 2.44 (s, 3H), 2.61-2.95 (m, 4H), 3.09-3.16 (m, 1H), 6.24-6.27 (d,J=8.67 Hz, 1H), 6.99 (dd, J=8.67, 2.26 Hz, 1H), 7.17-7.19 (m, 3H),7.39-7.44 (m, 1H), 7.47-7.52 (m, 2H). LCMS (12 minute method)[M+H]⁺=329/331 @ Rt 5.04 min (93%).

EXAMPLE 27D6-Chloro-1-(4-chlorophenyl)-3-(3-methylamino-propyl)-3,4-dihydro-1H-quinolin-2-one(21Do)

This was prepared from (20Da) (160 mg, 0.45 mmol) using the sametwo-step procedure described for (21Da) to provide the crude product,which was purified by preparative LCMS to give the racemate (52 mg). ¹HNMR (300 MHz, CDCl₃) (racemate) δ 1.57-1.67 (m, 1H), 1.73-1.75 (m, 2H),1.87-1.9 (m, 1H), 2.47 (s, 2H), 2.64 (s, 1H), 2.68-2.73 (m, 2H),2.81-2.89 (m, 1H), 3.07-3.13 (m, 3H), 6.27 (d, J=8.48 Hz, 1H), 7.02 (d,J=8.48 Hz, 1H), 7.14 (d, J=8.29 Hz, 2H), 7.19 (s, 1H), 7.47 (d, J=8.29Hz, 2H). LCMS (12 minute method) [M+H]⁺=363/365 @ Rt 5.4 min (72%).

EXAMPLE 28D6-Chloro-3-methyl-3-(3-methylamino-propyl)-1-p-tolyl-3,4-dihydro-1H-quinolin-2-one(21Dp)

This was prepared from (20Db) (490 mg, 1.34 mmol) using the same methodsdescribed for (21Da) to provide the racemate (470 mg). The racemate wasseparated into its individual enantiomers using chiral HPLC. ¹H NMR (300MHz, CDCl₃) (racemate) δ 1.25 (s, 3H), 1.50-1.65 (m, 4H), 2.39 (s, 3H),2.40 (s, 3H), 2.50-2.60 (m, 3H), 2.86 (d, J=16.01 Hz, 1H), 2.94 (d,J=16.01 Hz, 1H), 6.24 (d, J=8.67 Hz, 1H), 6.97 (dd, J=8.76, 2.35 Hz, 1),7.03 (d, J=8.10 Hz, 2H), 7.14 (d, J=2.26 Hz, 1H), 7.29 (d, J=7.91 Hz,2H); ¹H NMR (300 MHz, MeOD-d4) (isomer hemi-D-tartrate salt) δ 1.15 (s,3H), 1.50-1.75 (m, 4H), 2.32 (s, 3H), 2.51 (s, 3H), 2.78 (br, 2H), 2.84(d, J=16.20 Hz, 1H), 2.98 (m, 1H), 3.15-3.25 (m, 2H), 4.22 (s, 1H), 6.14(d, J=8.85 Hz, 1H), 6.90-6.70 (m, 3H), 7.19 (d, J=2.26 Hz, 1H), 7.25 (d,J=7.91 Hz, 2H). LCMS (12 minute method) [M+H]⁺=357/359 @Rt 5.43 min(100%).

EXAMPLE 29D6-Chloro-1-(4-chlorophenyl)-3-methyl-3-(3-methylamino-propyl)-3,4-dihydro-1H-quinolin-2-one(21Dq)

This was prepared from (20Db) (490 mg, 1.34 mmol) using the same methodsdescribed for (21 Da) to provide the racemate (425 mg). ¹H NMR (300 MHz,CDCl₃) (racemate) δ ppm 1.25 (s, 3H), 1.50-1.65 (m, 4H), 2.39 (s, 3H),2.40 (br, 1H), 2.50-2.60 (m, 2H), 2.87 (d, J=16.20 Hz, 1H), 2.95 (d,J=16.20 Hz, 1H), 6.23 (d, J=8.85 Hz, 1H), 7.00 (dd, J=8.57, 2.35 Hz,1H), 7.05-7.20 (m, 3H), 7.40-7.50 (m, 2H). LCMS (12 minute method)[M+H]⁺=377/379 (Rt 5.26 min (94%).

EXAMPLE 30D3-Methyl-3-(3-methylamino-propyl)-1-thiophen-2-yl-3,4-dihydro-1H-quinolin-2-one(22Da)

This was prepared from (19Db) (200 mg, 0.60 mmol) using the sametwo-step procedure described for (21Da) to provide the crude product,which was purified by SCX-2 to give the racemate (125 mg). ¹H NMR (300MHz, CDCl₃) (racemate) δ ppm 1.25 (s, 3H), 1.50-1.65 (m, 4H), 2.39 (s,3H), 2.50-2.60 (br, 2H), 2.88 (d, J=16.20 Hz, 1H), 2.97 (d, J=16.20 Hz,1H), 3.17 (br, 1H), 6.58 (dd, J=8.01, 0.85 Hz, 1H), 6.89 (dd, J=3.58,1.32 Hz, 1H), 6.95-7.15 (m, 3H), 7.16 (d, J=7.16 Hz, 1H), 7.32 (dd,J=5.65, 1.32 Hz, 1H). LCMS (12 minute method) [M+H]⁺=315 @Rt 4.35 min(98%).

EXAMPLE 31D3-Methyl-3-(3-methylamino-propyl)-1-thiophen-3-yl-3,4-dihydro-1H-quinolin-2-one(22Db)

This was prepared from (19Db) (200 mg, 0.60 mmol) using the sametwo-step procedure described for (21Da) to provide the crude product,which was purified by SCX-2-2 to give the racemate (128 mg). ¹H NMR (300MHz, CDCl₃) δ 1.24 (s, 3H), 1.50-1.65 (m, 4H), 2.40 (s, 3H), 2.50-2.60(m, 2H), 2.87 (d, J=15.82 Hz, 1H), 2.96 (d, J=15.82 Hz, 1H), 3.07 (br,1H), 6.45 (dd, J=8.10, 0.94 Hz, 1H), 6.92 (dd, J=5.09, 1.32 Hz, 1H),6.98 (td, J=7.35, 1.13 Hz, 1H), 7.07 (td, J=7.77, 1.60 Hz, 1H), 7.16 (d,J=7.35 Hz, 1H), 7.22 (dd, J=3.20, 1.32 Hz, 1H), 7.41 (dd, J=5.09, 3.20Hz, 1H). LCMS (12 minute method) [M+H]⁺=315 @Rt 4.29 min (100%).

Scheme 4D—Preparation of Intermediates

{3-[1-(4-Methoxy-benzyl)-3-methyl-2-oxo-6-phenyl-1,2,3,4-tetrahydro-quinolin-3-yl]-propyl}-methyl-carbamicacid tert-butyl ester (23D)

Step (i)

Sodium hydride (340 mg, 60% dispersion in mineral oil, 8.55 mmol, 1.3eq.) was added portionwise to a soln of (20Dc) (2.7 g. 6.57 mmol) in DMF(40 mL) at 0° C. The reaction mixture was left for 30 min at thistemperature and then 4-methoxybenzyl chloride (1.16 mL, 8.55 mmol, 1.3eq.) in DMF (1 mL) was added dropwise over 10 min. The reaction mixturewas warmed to rt slowly and after 1 h was poured into ethyl acetate (200mL) and extracted with water (3×50 mL). The organic layer was separated,dried over MgSO₄ and concentrated under vacuo. The crude product waspurified using automated chromatography (silica) (0 to 80% ethylacetatecyclohexane gradient) to provide the 4-methoxybenzyl protected6-bromo precursor (2.2 g, 63%).

Step (ii)

The product from Step (i) (100 mg, 0.23 mmol), phenylboronic acid (85mg, 0.70 mmol, 3 eq.), K₂CO₃ (138 mg, 1 mmol, 4.3 eq.) and Pd(PPh₃)₄ (11mg, 0.009 mmol, 0.04 eq.) were suspended in ethanol (1 mL) and water(0.6 mL). The reaction mixture was heated at 80° C. overnight, cooled tort and filtered through celite. The filtrate was poured into ethylacetate (100 mL) and water (50 mL) and extracted. The organic layer wasseparated, dried over MgSO₄ and concentrated to provide the product(23D) (120 mg, 98%) that was used without further purification.

Methyl-[3-(3-methyl-2-oxo-6-phenyl-1,2,3,4-tetrahydro-quinolin-3-yl)-propyl]-carbamicacid tert-butyl ester

Step (iii) & (iv)

A mixture of (23D) (120 mg, 0.23 mmol) and anisole (25 μL, 0.23 mmol) intrifluoroacetic acid (2.3 mL) was heated at 65° C. under nitrogen for 4h. The reaction mixture was concentrated under vacuo and the residue wasdissolved in methanol (2 mL). The methanol soln was applied to an SCX-2column (5 g) and the column washed with methanol (50 mL). The productwas eluted with 2N Et₃N in methanol (50 mL) and the basic soln wasconcentrated to provide3-Methyl-3-(3-methylamino-propyl)-6-phenyl-3,4-dihydro-1H-quinolin-2-one(72 mg, 100%). To a soln of this amine (72 mg, 0.23 mmol) in anhydrousTHF (2 mL) at 0° C. was added di-tert-butyl dicarbonate (53 mg, 97%,0.24 mmol) in one portion. The reaction mixture was warmed to rt andstirred for 3 h. The reaction mixture was poured into ethyl acetate (25mL) and water (10 mL) and extracted. The organic layer was separated,dried over MgSO₄ and concentrated to give the Boc protected precursor(95 mg, 100%). This material was used without further purification.

Scheme 4D EXAMPLES EXAMPLE 32D3-Methyl-3-(3-methylamino-propyl)-6-phenyl-1-p-tolyl-3,4-dihydro-1H-quinolin-2-one(24D)

This was prepared from the above Boc protected precursor (95 mg, 0.23mmol) using the same two-step procedure described above (19Da to 21Da)to provide the crude product, which was purified by SCX-2 to give theracemate (53 mg). ¹H NMR (300 MHz, CDCl₃) (racemate) δ 1.29 (s, 3H),1.50-1.70 (m, 4H), 2.42 (s, 6H), 2.55-2.65 (m, 2H), 2.94 (d, J=15.64 Hz,1H), 3.04 (d, J=15.64 Hz, 1H), 3.18 (br, 1H), 6.38 (d, J=8.29 Hz, 1H),7.09 (d, J=8.10 Hz, 2H), 7.29 (m, 4H), 7.41 (m, 3H), 7.54 (m, 2H). LCMS(12 minute method) [M+H]⁺=399 @Rt 6.06 min (100%).

The following examples illustrate compounds of of Formulae (IE) aboveand methods for their preparation.

Preparation of Intermediates

1,1-Dimethylethyl (3S)-3-aminopyrrolidine-1-carboxylate a)1,1-Dimethylethyl (3R)-3-hydroxypyrrolidine-1-carboxylate

Solid ditert-butyldicarbonate (38.8 g, 178 mmol) was added in portionsover 15 minutes to a stirred solution of (3R)-pyrrolidin-3-olhydrochloride (20 g, 162 mmol), triethylamine (24.8 mL, 178 mmol) and4-(dimethylamino)-pyridine (20 mg) in dry dichloromethane (300 mL).After stirring for 2 hours at room temperature, the mixture was washedwith aqueous citric acid, then brine. The organic extracts were dried(MgSO₄), filtered and evaporated in vacuo to give an oil. This waspurified by flash chromatography on silica, eluting with ethylacetate/cyclohexane (20:80 to 60:40), to give the title compound as asolid.

b) 1,1-Dimethylethyl(3R)-3-[(methylsulfonyl)oxy]-pyrrolidine-1-carboxylate

Methanesulfonyl chloride (5.26 mL, 68 mmol) was added dropwise over 5minutes to a stirred solution of 1,1-dimethylethyl(3R)-3-hydroxypyrrolidine-1-carboxylate (10.6 g, 56.7 mmol) andtriethylamine (11.8 mL, 85 mmol) in dichloromethane (250 mL) at −10° C.After stirring for 1 hour at 0° C., the reaction was quenched byaddition of water. The organic phase was washed with brine, dried(MgSO₄), filtered and evaporated in vacuo to give an oil. This waspurified by flash chromatography on silica, eluting with ethylacetate/cyclohexane (25:75 to 50:50), to give the title compound as anoil.

c) 1,1-Dimethylethyl (3S)-3-azidopyrrolidine-1-carboxylate

Sodium azide (4.4 g, 67.4 mmol) was added to a solution of1,1-dimethylethyl (3R)-3-[(methylsulfonyl)oxy]-pyrrolidine-1-carboxylate(14.3 g, 54 mmol) in dry dimethylformamide (75 mL) and the resultantsuspension heated at 65° C. for 8 hours. After cooling to roomtemperature, the reaction mixture was diluted with water and extractedinto diethyl ether. The organic phase was washed two further times withwater, then brine. The organic extracts were dried (MgSO₄), filtered andevaporated in vacuo to give an oil. This was purified by flashchromatography on silica, eluting with diethyl ether/cyclohexane (20:80to 40:60), to give the title compound as an oil.

d) 1,1-Dimethylethyl (3S)-3-aminopyrrolidine-1-carboxylate

A mixture of 1,1-dimethylethyl (3S)-3-azidopyrrolidine-1-carboxylate(9.0 g, 2.97 mmol) and 5% palladium-on-carbon (0.70 g) in methanol (150mL) was hydrogenated in a Parr apparatus at 65 p.s.i. for 4 hours. Thecatalyst was removed by filtration through Celite and the solventevaporated in vacuo to give an oil. The resultant title compound wasused in subsequent reactions without further purification.

1,1-Dimethylethyl (3R)-3-aminopyrrolidine-1-carboxylate was similarlyprepared as described above, from (3S)-pyrrolidin-3-ol.

1,1-Dimethylethyl(3S)-3-[(1-methylethyl)amino]-pyrrolidine-1-carboxylate

A mixture of 1,1-dimethylethyl (3S)-3-aminopyrrolidine-1-carboxylate(3.0 g) and 5% palladium-on-carbon (0.35 g) in methanol (75 mL) andacetone (15 mL) was hydrogenated in a Parr apparatus at 65 p.s.i. for 3hours. The catalyst was removed by filtration through Celite and thesolvent evaporated in vacuo to give an oil. The resultant title compoundwas used in subsequent reactions without further purification.

¹H NMR (300 MHz, CDCl₃) δ_(H): 1.11-1.19 (m, 6H), 1.45 (s, 9H),1.55-1.75 (m, 1H) 2.01-2.15 (m, 1H), 2.80-2.92 (m, 1H), 2.93-3.05 (m,1H), 3.25-3.70 (m, 4H).

The following secondary amines were similarly prepared by reductivealkylation of 1,1-dimethylethyl (3S)-3-aminopyrrolidine-1-carboxylatewith the appropriate aldehyde or ketone:

-   1,1-Dimethylethyl (3S)-3-(cyclopentylamino)pyrrolidine-1-carboxylate-   1,1-Dimethylethyl    (3S)-3-[(cyclohexylmethyl)amino]-pyrrolidine-1-carboxylate

1,1-Dimethylethyl(3S)-3-({[2-(trifluoromethyl)phenyl]-methyl}amino)pyrrolidine-1-carboxylate

Method A

a)(3S)-N-{(E)-[2-(Trifluoromethyl)phenyl]methylidene}-pyrrolidin-3-amine

3(S)-Pyrrolidin-3-amine (0.45 g, 5.2 mmol) andtrifluoromethylbenzaldehyde (0.87 g, 5.0 mmol), a crystal of4-toluenesulphonic acid and toluene were refluxed with stirring for oneday, using a Dean and Stark apparatus. The solution was evaporated invacuo to give the title compound as a brown oil (M+H=243).

b) 1,1-Dimethylethyl(3S)-3-({(E)-[2-(trifluoromethyl)-phenyl]methylidene}amino)pyrrolidine-1-carboxylate

(3S)-N-{(E)-[2-(Trifluoromethyl)phenyl]methylidene}-pyrrolidin-3-amine(1.21 g, 5 mmol) was dissolved in dichloromethane (50 mL), anddi-tert-butyl dicarbonate (1.1 g, 5.05 mmol) followed by DMAP (60 mg,0.5 mmol) was added. After stirring under nitrogen for 4 hours, thesolution was evaporated in vacuo to give the title compound as a brownoil (M+H=343).

c) 1,1-Dimethylethyl(3S)-3-({[2-(trifluoromethyl)-phenyl]methyl}amino)pyrrolidine-1-carboxylate

1,1-Dimethylethyl(3S)-3-({(E)-[2-(trifluoromethyl)-phenyl]methylidene}amino)pyrrolidine-1-carboxylate(1.71 g, 5 mmol) was hydrogenated in the presence of 5% palladium oncarbon (250 mg) at 65 psi in ethanol (60 mL). After 3.5 hours, thecatalyst was filtered off and the filtrate evaporated in vacuo to givean oil. The oil was purified by automated flash chromatography oversilica, eluting with 10% ethyl acetate in cyclohexane (10:90 to 50:50),to give the title compound as a colourless oil (1.0 g, 58%; M+H=345).

Method B

a) (3S)-N-{[2-(Trifluoromethyl)phenyl]methyl}pyrrolidin-3-amine

A mixture of 3(S)-pyrrolidin-3-amine (4 g, 46.5 mmol),2-trifluoromethylbenzaldehyde (9.1 g, 46.5 mmol), 5% palladium on carbon(0.4 g) and ethanol (150 mL) was hydrogenated at 60 psi for 3 hoursusing a Parr hydrogenator. The catalyst was filtered off and thefiltrate evaporated in vacuo to give the title compound as an oil. MS:[M+H]=245.

b) 1,1-Dimethylethyl(3S)-3-({[2-(trifluoromethyl)-phenyl]methyl}amino)pyrrolidine-1-carboxylate

(3S)-N-{[2-(Trifluoromethyl)phenyl]methyl}pyrrolidin-3-amine (12 g, 49.2mmol) was dissolved in dichloromethane (120 mL), then di-tert-butyldicarbonate (10.7 g, 49.2 mmol) and DMAP (40 mg, 0.33 mmol) were added.After stirring under nitrogen for 1 day, the solution was evaporated invacuo to give an oil. The oil was purified by automated flashchromatography over silica, eluting with ethyl acetate in cyclohexane(0:100 to 40:60), to give the title compound as a colourless oil.

MS: [M+H]=345.

1,1-Dimethylethyl(3S)-3-({[4-fluoro-2-(trifluoromethyl)-phenyl]methyl}amino)pyrrolidine-1-carboxylate

1,1-Dimethylethyl (3S)-3-aminopiperidine-1-carboxylate (5 g) and4-fluoro-2-(trifluoromethyl)benzaldehyde (5.15 g, 26.8 mmol)were allowedto stir in methanol for 16 h at room temperature. Sodium borohydride(1.62 g, 26.8 mmol) was then added portionwise. The resulting solutionwas further stirred for 2 h at room temperature. The solvent wasevaporated in vacuo, water was added, and the solution extracted withdichloromethane. The organic extracts were absorbed onto a methanolwashed cationic ion exchange resin (Isolute™ SCX-2). The basiccomponents were recovered from the column by elution with 7N ammonia inmethanol. The resultant solution was concentrated in vacuo to yield thedesired compound as an oil. This was further purified by columnchromatography on silica gel, eluting with ethyl acetate/iso-hexane(0:100 to 40:60). The title compound was used in subsequent reactionswithout further purification.

¹H NMR (300 MHz, CDCl₃) δ_(H): 7.37-7.28 (m, 2H), 7.24-7.20 (m, 1H),3.80 (s, 2H), 3.52-3.48 (m, 2H), 3.32 (m, 3H), 3.12 (m, 1H), 2.08-2.0(m, 1H), 1.75 (m, 1H), 1.45 (s, 9H).

The following secondary amines were similarly prepared by reductivealkylation of 1,1-dimethylethyl (3S)-3-aminopiperidine-1-carboxylatewith the appropriate benzaldehyde:

-   1,1-Dimethylethyl    (3S)-3-{[(3,5-dichloro-phenyl)methyl]-amino}pyrrolidine-1-carboxylate.-   1,1-Dimethylethyl    (3S)-3-{[(5-fluoro-2-(trifluoromethyl)-phenyl)methyl]amino}pyrrolidine-1-carboxylate.-   1,1-Dimethylethyl    (3S)-3-{[(2-chloro-4-fluoro-phenyl)-methyl]amino}pyrrolidine-1-carboxylate.

EXAMPLE 1E(3S)-N-(1-Methylethyl)-N-{[3,5-dichlorophenyl]-methyl}pyrrolidin-3-amineD-tartrate a) 1,1-Dimethylethyl(3S)-3-((1-methylethyl)-{[3,5-dichlorophenyl]methyl}amino)-pyrrolidine-1-carboxylate

To a solution of 1,1-dimethylethyl(3S)-3-[(1-methylethyl)amino]-pyrrolidine-1-carboxylate (1 g, 4.4 mmol)and 3,5-dichlorobenzaldehyde (1.53 g, 8.77 mmol) intrimethylorthoformate (10 mL) at room temperature under a nitrogenatmosphere was added portionwise sodium triacetoxyborohydride (1.3 g,6.1 mmol). The reaction was stirred at room temperature for 72 hours,then evaporated to dryness in vacuo. The residue was taken up in aqueoussaturated sodium hydrogen carbonate/dichloromethane mixture. The aqueouslayer was further extracted with dichloromethane (3X), and the combinedorganic layers dried (MgSO₄) and evaporated to dryness in vacuo. Theresulting residue was dissolved in methanol and filtered through acationic ion exchange resin (Isolute™ SCX-2). The basic components wererecovered from the column by elution with 2N ammonia in methanol. Thissolution was concentrated in vacuo to yield the desired compound as ayellow oil that was used in the next step without further purification.¹H NMR (300 MHz, CDCl₃) δ_(H): 0.95-1.04 (m, 6H), 1.45 (s, 9H),1.56-1.77 (m, 1H), 1.8-1.94 (m, 1H), 2.9-3.09 (m, 2H), 3.11-3.25 (m,1H), 3.32-3.56 (m, 3H), 3.59 (s, 2H), 7.15-7.27 (m, 3H). MS:[M+H]=387/389/391.

b)(3S)-N-(1-Methylethyl)-N-{[3,5-dichlorophenyl)methyl}-pyrrolidin-3-amineD-tartrate

1,1-Dimethylethyl(3S)-3-((1-methylethyl)-{[3,5-dichlorophenyl]methyl}amino)pyrrolidine-1-carboxylate(1.36 g, 3.51 mmol) was dissolved in a mixture of dichloromethane andtrifluoroacetic acid (10 mL, 2:1) and stirred at room temperature for 30minutes. The reaction solution was concentrated in vacuo and redissolvedin MeOH. This solution was filtered through a cationic ion exchangeresin (Isolute™ SCX-2). The basic components were isolated by elutionwith 2N ammonia in methanol and further purified by UV guided prep-LC.The desired compound was isolated from the acidic prep-LC mobile phasevia a cationic ion exchange resin as described above. After evaporationin vacuo the residue was dissolved in hot cyclohexane (5 mL) and to thiswas added an equimolar amount of D-tartaric acid (450 mg), dissolved ina minimal amount of hot isopropanol. The solution was evaporated invacuo to yield the title compound as a solid. ¹H NMR (300 MHz, d6-DMSO)δ_(H): 0.95-0.99 (m, 6H), 1.58-1.71 (m, 1H), 1.91-2.00 (m, 1H),2.76-2.91 (m, 2H), 2.97-3.07 (m, 1H), 3.18-3.25 (m, 2H), 3.55-3.67 (m,4H), 3.95 (s, 2H), 7.37-7.38 (m, 2H), 7.43-7.45 (m, 1H). MS:[M+H]=287/289/291.

The following Examples were similarly prepared as described above forExample 1E, by reductive alkylation of 1,1-dimethylethyl(3S)-3-[(1-methylethyl)amino]-pyrrolidine-1-carboxylate with theappropriate substituted benzaldehyde:

EXAMPLE 2E(3S)-N-(1-Methylethyl)-N-}[2-(methylthio)phenyl[methyl}-pyrrolidin-3-aminefumarate

¹H NMR (300 MHz, CD₃OD) δ_(H): 0.99 (s, 6H), 2.06 (m, 1H), 2.37 (s, 3H),3.01-2.85 (m, 1H), 3.18-3.06 (m, 1H), 3.46-3.19 (m, 4H), 3.67 (dd, 2H),6.60 (s, 2H), 7.10-7.02 (m, 1H), 7.20-7.11 (m, 2H), 7.40 (dd, 1H); MS:[M+H]=265.

The following Examples were similarly prepared as described above forExample 1E, by reductive alkylation of 1,1-dimethylethyl(3S)-3-[(cyclohexylmethyl)amino]-pyrrolidine-1-carboxylate with theappropriate substituted benzaldehyde:

EXAMPLE 3E(3S)-N-(Cyclohexylmethyl)-N-{[2-(methylthio)phenyl]-methyl}pyrrolidin-3-aminefumarate

¹H NMR (300 MHz, CD₃OD) δ_(H): 0.86-0.69 (s, 3H), 1.22-1.12 (m, 3H),1.41-1.29 (m, ¹H), 1.84-1.67 (m, 5H), 2.16-1.95 (m, 2H), 2.34 (d, 2H),2.38 (s, 3H), 3.23-3.05 (m, 1H), 3.44-3.28 (m, 4H), 3.78-3.55 (m, 2H),6.70 (s, 2H), 7.16 (s, 2H), 7.35-7.32 (m, 1H); MS: [M+H]=319.

EXAMPLE 4E(3S)-N-(Cyclohexylmethyl)-N-[(2-fluorophenyl)methyl]-pyrrolidin-3-aminefumarate

¹H NMR (300 MHz, CD₃OD) δ_(H): 0.83-0.75 (s, 6H), 1.24-1.17 (m, 3H),1.48-1.42 (m, 1H), 1.85-1.68 (m, 5H), 2.03-1.92 (m, 1H), 2.17-2.10 (m,1H), 2.35 (d, 2H), 3.25-3.05 (m, 1H), 3.44-3.32 (m, 4H), 3.81-3.62 (m,2H), 6.71 (s, 2H), 7.20-7.05 (m, 2H), 7.33-7.27 (m, 1H), 7.47-7.42 (m,1H); MS: [M+H]=291.

EXAMPLE 5E(3S)-N-[(2-Chlorophenyl)methyl]-N-(cyclohexylmethyl)-pyrrolidin-3-aminefumarate

¹H NMR (300 MHz, CD₃OD) δ_(H): 0.89-0.77 (m, 2H), 1.24-1.13 (m, 3H),1.36 (d, 6H), 1.49-1.42 (m, 1H), 1.83-1.68 (m, 5H), 2.15-1.93 (m, 2H),2.35 (d, 2H), 3.20-3.06 (m, 1H), 3.33-3.23 (m, 4H), 3.75-3.42 (m, 2H),4.69-4.61 (m, 1H), 6.70 (s, 2H), 6.98-6.88 (m, 2H), 7.35 (d, 1H),7.50-7.19 (m, 1H); MS: [M+H]=307.

EXAMPLE 6E(3S)-N-(Cyclohexylmethyl)-N-({2-[1-(methylethyl)oxy]-phenyl}methyl)pyrrolidin-3-aminefumarate

¹H NMR (300 MHz, CD₃OD) δ_(H): 0.89-0.77 (m, 2H), 1.24-1.13 (m, 3H),1.36-1.34 (dd, 6H), 1.49-1.42 (m, 1H), 1.83-1.68 (m, 5H), 1.93 (m, 2H,m), 2.35 (d, 2H), 3.20-3.06 3.20-3.06 (m, 1H), 3.33-3.23 (m, 4H),3.75-3.42 (m, 2H), 4.69-4.61 (m, 1H), 6.70 (s, 2H), 6.98-6.88 (m, 2H),7.35 (d, 1H), 7.50-7.19 (m, 1H); MS: [M+H]=331.

EXAMPLE 7E(3S)-N-{[5-Fluoro-2-(trifluoromethyl)phenyl]methyl}-N-(tetrahydro-2H-pyran-4-yl)pyrrolidin-3-amineD-tartrate a) 1,1-Dimethylethyl(3S)-3-[(tetrahydro-2H-pyran-4-yl)amino]pyrrolidine-1-carboxylate

Neat tetrahydro-4H-pyran-4-one (18.7 g, 100 mmol) and 1,1-dimethylethyl(3S)-3-aminopyrrolidine-1-carboxylate (26.1 g, 140.1 mmol) were stirredtogether for 20 minutes prior to addition of anhydrous dichloroethane(140 mL). The solution was then cooled to 0° C. under nitrogen andstirred as sodium triacetoxyborohydride (59.2 g, 281 mmol) was addedportionwise. The reaction was allowed to warm to room temperature andstirred for 5 days, after which the reaction solution was carefullypoured onto ice-cold aqueous sodium hydrogen carbonate solution. Thephases were separated and the aqueous phase washed with dichloromethane.The combined organic phases were dried (MgSO₄) and concentrated invacuo. The crude product was purified by automated flash chromatographyon silica, eluting with methanol in ethyl acetate (0:100 to 30:70), toprovide the title compound as an off-white solid. ¹H NMR (300 MHz,d6-DMSO) δ_(H): 1.13-1.29 (m, 2H), 1.39 (s, 9H), 1.55-1.65 (m, 1H),1.68-1.81 (m, 2H), 1.87-2.00 (m, 1H), 2.64 (sep, 1H), 2.91 (sex, 1H),3.10-3.45 (m, 6H), 3.81 (dt, 2H). MS: [M+H]=271, [M+H−tBu]=215.

b)(3S)-N-{[5-Fluoro-2-(trifluoromethyl)phenyl]methyl)-N-(tetrahydro-2H-pyran-4-yl)pyrrolidin-3-amineD-tartrate

To a stirred solution of 1,1-dimethylethyl(3S)-3-[(tetrahydro-2H-pyran-4-yl)amino]pyrrolidine-1-carboxylate (1.12g, 4.2 mmol) and 5-fluoro-2-(trifluoromethyl)benzaldehyde (4.56 g, 23.8mmol) in anhydrous dichloroethane (50 mL) was added portionwise sodiumtriacetoxyborohydride (3.86 g, 18.3 mmol). The reaction mixture wasstirred at room temperature under nitrogen and the reaction progress wasfollowed by MS. After 2 days more reagents were added:5-fluoro-2-(trifluoromethyl)benzaldehyde (0.98 g, 5.1 mmol) and sodiumtriacetoxyborohydride (3.00 g, 14.2 mmol), and after a further 2 daysthe reaction was found to be complete. The reaction solution wascarefully poured onto ice-cold saturated aqueous sodium hydrogencarbonate solution and filtered through a PTFE hydrophobic frit. Theorganic phase was concentrated in vacuo and the residue redissolved inmethanol. The methanolic solution was filtered through a cationic ionexchange resin (Isolute™ SCX-2) and the basic components isolated byelution with 2N ammonia in methanol. After concentrating in vacuo, theresidue was redissolved in dichloromethane/trifluoro-acetic acid (2:1)and allowed to stir at room temperature for 4 hours. The reactionmixture was concentrated in vacuo and redissolved in methanol. Themethanolic solution was filtered through a cationic ion exchange resin(Isolute™ SCX-2) and the basic components isolated by elution with 2Nammonia in methanol. The crude product was purified by UV guidedprep-LC, and the desired compound collected from the acidic prep-LCmobile phase via a cationic ion exchange resin, as described above. Thebasic product was dissolved in hot cyclohexane and to this was added anequimolar amount of D-tartaric acid dissolved in a minimal amount of hotisopropanol. The solution was allowed to cool overnight, and the nextday the resultant solid was filtered off and dried in vacuo, to yieldthe title compound as a white crystalline solid. ¹H NMR (300 MHz,d6-DMSO) δ_(H): 1.40-1.80 (m, 5H), 1.91-2.06 (m, 1H), 2.61-2.74 (m, 1H),2.81-2.93 (dd, 1H), 2.97-3.11 (dt, 1H), 3.12-3.31 (m, 4H), 3.69-3.96 (m,7H), 7.49-7.61 (m, 2H), 7.90-7.99 (m, 1H). MS: [M+H]=347.

The following Examples were similarly prepared from 1,1-dimethylethyl(3S)-3-[(tetrahydro-2H-pyran-4-yl)amino]pyrrolidine-1-carboxylate andthe appropriate benzaldehyde, as described above for Example 7E:

EXAMPLE 8E(3S)-N-{[2-(Trifluoromethyl)phenyl]methyl}-N-(tetrahydro-2H-pyran-4-yl)pyrrolidin-3-aminehemi-D-tartrate

¹H NMR (300 MHz, d6-DMSO) δ_(H): 1.35-1.75 (m, 5H), 1.90-2.04 (m,1H),2.63-2.75 (m, 1H), 2.76-2.86 (m, 1H), 2.94-3.03 (m, 1H), 3.10-3.25 (m,4H), 3.67-3.90 (m, 6H), 7.43 (t, 1H), 7.66 (t, 2H), 7.92 (d, 1H); MS:[M+H]=329.

EXAMPLE 9E(3S)-N-(1-Methylethyl)-N-{[2-(trifluoromethyl)-5-fluorophenyl]methyl}pyrrolidin-3-aminefumarate a) 1,1-Dimethylethyl(3S)-3-((1-methylethyl)-{[2-(trifluoromethyl)-5-fluorophenyl]methyl}amino)-pyrrolidine-1-carboxylate

A solution of 1,1-dimethylethyl(3S)-3-[(1-methylethyl)amino]pyrrolidine-1-carboxylate (0.34 g, 1.5mmol) and 2-(trifluoromethyl)-5-fluorobenzyl bromide (0.58 g, 2.25 mmol)in acetonitrile (5 mL) was heated at reflux with anhydrous potassiumcarbonate (0.41 g, 3 mmol) for 24 hours. The reaction mixture wascooled, diluted with ethyl acetate and washed with water. The organicextracts were washed with brine, dried (MgSO₄), filtered and evaporatedin vacuo to give an oil. This was purified by flash chromatography onsilica, eluting with ethyl acetate/cyclohexane (0:100 to 10:90), to givethe title compound as an oil.

b)(3S)-N-(1-Methylethyl)-N-{[2-(trifluoromethyl)-5-fluorophenyl]methyl}pyrrolidin-3-aminefumarate

A solution of 1,1-dimethylethyl(3S)-3-((1-methylethyl)-{[2-(trifluoromethyl)-5-fluorophenyl]-methyl}amino)-pyrrolidine-1-carboxylate(0.26 g) in a mixture of trifluoroacetic acid (2 mL), dichloromethane (8mL) and water (0.2 mL) was stirred at room temperature for 3 hours. Thereaction mixture was evaporated in vacuo. The crude mixture was taken upin methanol and absorbed onto an SCX-2 ion exchange cartridge. Afterinitially washing with methanol, the product was eluted with 2Mmethanolic ammonia and the collected fractions evaporated in vacuo. Thecrude product was taken up in methanol and fumaric acid (1 equiv.) inmethanol added. The solvent was removed in vacuo and the resultant gumtriturated with diethyl ether. The solid formed was filtered off anddried in vacuo at 50° C. to yield the title compound as an off-whitemicrocrystalline solid. ¹H NMR (300 MHz, CD₃OD) δ_(H): 1.09 (d, 3H),1.10 (d, 3H), 1.87 (m, 1H), 2.15 (m, 1H), 3.01 (m, 2H), 3.23 (m, 1H),3.38 (m, 2H), 3.81 (m, 1H), 3.91 (s, 2H), 6.70 (s, 2H), 7.15 (dt, 1H),7.73 (m, 2H); MS: [M+H]=305.

The following Examples were similarly prepared as described for Example9E, using the appropriate substituted benzyl bromide in step b) above:

EXAMPLE 10E(3S)-N-([1,1′-Biphenyl]-2-ylmethyl)-N-(1-methylethyl)-pyrrolidin-3-aminefumarate

¹H NMR (300 MHz, CD₃OD) δ_(H): 0.95 (d, 6H), 1.75 (m, 1H), 1.91 (m, 1H),2.75 (dd, 1H), 2.93 (sept, 1H), 3.10 (m, 2H), 3.25 (m, 1B), 3.60 (m,3H), 6.70 (s, 2H), 7.17 (dd, 1H), 7.25-7.48 (m, 7H), 7.67 (d, 1H); MS:[M+H]=295.

EXAMPLE 11E Methyl((3S)-pyrrolidin-3-yl{[2-(trifluoromethyl)phenyl]-methyl}amino)acetateD-tartrate

60% Sodium hydride oil dispersion (39 mg, 0.95 mmol) was added to1,1-dimethylethyl(3S)-3-({[2-(trifluoromethyl)-phenyl]methyl}amino)pyrrolidine-1-carboxylate(250 mg, 0.73 mmol) in DMF (5 mL). After heating at 50° C. for 1 hourunder nitrogen, methyl bromoacetate (123 mg, 0.73 mmol) was added. Afterheating overnight at 50° C. overnight, excess water was added and theproduct was extracted into ether. The ether was washed with water, dried(MgSO₄) and evaporated in vacuo to give an oil (460 mg). The oil wasdissolved in dichloromethane (5 mL) and trifluoroacetic acid (0.5 mL)was added. After stirring for 1 day, the solution was evaporated invacuo to give an oil. The oil was purified using preparative LCMS togive the product as the acetate salt, which was converted to the freebase by absorption onto a cationic ion exchange resin (Isolute™ SCX-2)and eluting the basic fractions with 2N ammonia in methanol. Theresultant oil was converted to the D-tartaric acid salt (crystallisedfrom ethanol/diethyl ether) to give the title compound as a white solid.¹H NMR(300 MHz, CD₃OD) δ_(H): 1.84-196 (m, 1H), 2.06-2.14 (m, 1H),3.06-3.37 (2×m,6H), 3.57 (s, 3H), 3.77-3.86 quin,1H), 3.91-4.06 (q, 2H),4.29 (s, 2H), 7.32-7.36 (t, 1H), 7.49-7.54 (t, 1H), 7.56-7.59 (d, 1H),7.76-7.89 (d, 1H); MS: [M+H]=317.

The following Examples were prepared from 1,1-dimethylethyl(3S)-3-aminopyrrolidine-1-carboxylate by initial reductive alkylationwith 2-methylpropanaldehyde, followed by a second reductive alkylationwith the appropriate benzaldehyde and subsequent deprotection.

EXAMPLE 12E(3S)-N-{[2-(Methoxy)phenyl]methyl}-N-(2-methylpropyl)pyrrolidin-3-aminefumarate

¹H NMR (300 MHz, CD₃OD) δ_(H): 0.82 (dd, 6H), 1.66 (sept, 1H), 1.79-1.92(m, 1H), 1.92-2.06 (m, 1H), 2.19-2.22 (m, 2H), 2.96-3.13 (m, 2H),3.18-3.31 (m, 2H), 3.59-3.67 (m, 2H), 3.74 (s, 3H), 6.59 (s, 2H),6.80-6.87 (m, 2H), 7.11-7.18 (m, 1H), 7.25 (dd, 1H); MS: [M+H]=263.

The following Examples were prepared from 1,1-dimethylethyl(3S)-3-({[2-(trifluoromethyl)phenyl]-methyl}amino)pyrrolidine-1-carboxylateby reductive alkylation with the appropriate aldehyde or ketone andsubsequent deprotection.

EXAMPLE 13E(3S)-N-(1-Methylethyl)-N-{[2-(trifluoromethyl)-phenyl]methyl}pyrrolidin-3-aminefumarate

¹H NMR (300 MHz, CD₃OD) δ_(H): 7.98-8.00 (d, 1H), 7.60-7.68 (d+t, 2H),7.38-7.43(t, 1H), 6.70 (s, 2H), 3.91 (bs, 2H), 3.74-3.85 (m, 1H),3.17-3.40 (M, 5H), 2.96-3.10 (m,3H), 2.08-2.18 (m, 1H), 1.82-1.96(m,1H), 1.08-1.11 (dd, 6H); MS: [M+H]=287.

EXAMPLE 14E(3S)-N-Ethyl-N-{[2-(trifluoromethyl)phenyl]methyl}-pyrrolidin-3-aminefumarate

¹H NMR (300 MHz, CD₃OD) δ_(H): 8.00-8.03 (d, 1H), 7.67-7.76 (d+t, 2H),7.47-7.52 (t, 1H), 6.77 (s, 2H), 3.89-4.03 (q, 2H), 3.65-3.75 (quin,2H), 3.43-3.53 (m, 2H), 3.28-3.41 (m, 1H), 3.17-3.23 (m, 1H), 2.73-2.84(q, 2H), 2.19-2.30 (m, 2H), 2.19-2.30 (m, 1H), 1.98-2.14 (m, 1H),1.10-1.15 (t, 3H); MS: [M+H]=273.

EXAMPLE 15E(3S)-N-Propyl-N-{[2-(trifluoromethyl)phenyl]methyl}-pyrrolidin-3-aminefumarate

¹H NMR (300 MHz, CD₃OD) δ_(H): 7.92-7.94 (d, 1H), 7.60-7.69) d+t, 2H),7.40-7.45 (t, 1H), 6.69-6.73 (s, 2H), 3.82-3.98 (q, 2H), 5.59-3.69(quin,1H), 3.35-3.45 (m, 2H), 2.80-3.21 (m, 1H), 3.08-3.15 (m, 1H), 2.54-2.59(q, 2H), 2.10-2.21 (m, 1H), 1.90-2.06 (m, 1H), 1.44-1.56 (quin, 2H),0.86-0.91 (T, 3H); MS: [M+H]=287.

EXAMPLE 16E(3S)-N-(Cyclohexylmethyl)-N-{[2-(trifluoromethyl)-phenyl]methyl}pyrrolidin-3-aminefumarate

¹H NMR (300 MHz, CD₃OD) δ_(H): 77.89-7.92 (d, 1H), 7.61-7.70 (d+t, 2H),7.41-7.49 (t, 1H), 6.70 (s, 2H), 3.81-3.95 (q, 2H), 3.56-3.67 (quin,1H), 3.31-3.43 (m, 2H), 3.14-3.23 (m, 1H), 3.04-3.11 (m, 1H), 2.39-2.41(d, 2H), 2.06-2.13 (m, 1H), 1.70-2.01 (m, 6H), 1.34-1.46 (m, 1H),1.12-1.23 (m, 1H), 0.83-0.89 (m, 2H); MS: [M+H]=341.

EXAMPLE 17E(3S)-N-Butyl-N-{[2-(trifluoromethyl)phenyl]methyl}-pyrrolidin-3-aminefumarate

¹H NMR (300 MHz, CD₃OD) δ_(H): 7.91-7.94 (d, 1H), 7.60-7.69 (m, 2H),7.40-7.45 (t, 1H), 6.70 (s, 2H), 3.82-3.96 (q, 2H), 3.59-3.69 (quin,1H), 3.32-3.50 (m, 2H), 3.22-3.29 (m, 1H), 3.09-3.15 (q, 1H), 2.58-2.63(t, 2H), 2.10-2.21 (m, 1H), 1.90-2.04 (m, 1H), 1.42-1.51 (m, 2H),1.17-1.37 (m, 2H), 0.87-0.91 (t, 3H); MS: [M+H]=301.

EXAMPLE 18E(3S)-N-(2-Ethylbutyl)-N-{[2-(trifluoromethyl)phenyl]-methyl}pyrrolidin-3-aminesesquifumarate

¹H NMR (300 MHz, CD₃OD) δ_(H): 7.77-7.80 (d, 1H), 7.49-7.60 (m, 2H),7.29-7.34 (t, 1H), 6.60 (s, 1.5H), 3.70-3.81 (q, 2H), 3.46-3.57 (quin,1H), 3.20-3.33 (m, 2H), 2.94-3.13 (m, 2H), 2.32-2.34 (d, 2H), 1.97-2.07(m 1H), 1.78-1.91 (m, 1H), 1.05-1.40 (m, 5H), 0.69-0.76 (m, 6H). MS:[M+H]=329.

EXAMPLE 19E(3S)-N-{[2-(Trifluoromethyl)phenyl]methyl}-N-(3,3,3-trifluoropropyl)pyrrolidin-3-aminefumarate

¹H NMR (300 MHz, CD₃OD) δ_(H): 7.76-7.78 (d, 1H), 7.50-7.60 (d+t, 2H),7.32-7.37 (t, 1H), 6.58 (s, 2H), 3.75-3.89 (q, 2H), 3.48-3.59 (quin,1H), 3.126-3.22 (m, 1H), 2.98-3.05 (dd, 1H), 2.75-2.80 (t, 2H),2.18-2.34 (m, 2H), 2.02-2.13 (m, 1H), 1.80-1.93 (m, 1H); MS: [M+H]=341.

EXAMPLE 20E(3S)-N-(Furan-2-ylmethyl)-N-{[2-(trifluoromethyl)phenyl]-methyl}pyrrolidin-3-amineD-tartrate

¹H NMR (300 MHz, CD₃OD) δ_(H): 7.83-7.86 (d, 1H), 7.49-7.58 (t+s, 2H),7.29-7.38 (m, 2H), 6.23-6.26 (m, 1H), 6.14-6.15 (m, 1H), 4.30 (s, 2H),3.78-3.91 (q, 2H), 3.66-3.67 (m, 2H), 3.25-3.55 (m, 3H), 2.30-3.17 (m,2H), 2.05-2.16 (m, 1H), 1.83-1.96 (m, 1H); MS: [M+H]=325.

EXAMPLE 21E(3S)-N-[3-(Methylthio)propyl]-N-{[2-(trifluoromethyl)-phenyl]methyl}pyrrolidin-3-amineD-tartrate

¹H NMR (300 MHz, CD₃OD) δ_(H): 7.90-7.92 (d,1H), 7.61-7.70 (d+t, 2H),7.41-7.46 (t, 1H), 4.42 (s, 2H), 3.84-3.97 (q, 2H), 3.59-3.69 (quin,1H), 3.38-3.47 (m, 2H), 3.19-3.29 (m, ¹H), 3.09-3.16 (m, 1H), 2.70-2.77(dt, 2H), 2.48-2.52 (t, 2H), 2.08-2.21 (m, 1H), 1.89-2.08 (s+m, 4H),1.69-1.79 (quin, 2H); MS: [M+H]=333.

EXAMPLE 22EN-(Phenylmethyl)-N-[(3S)-pyrrolidin-3-yl]-N-{[2-(trifluoromethyl)phenyl]methyl}aminefumarate

¹H NMR (300 MHz, CD₃OD) δ_(H): 7.93-7.96 (d, 1H), 7.60-7.68 (q, 2H),7.23-7.44 (m, 6H), 6.69 (s, 2H), 3.83-3.94 (s,2H), 3.61-3.80 (m, 3H),3.32-3.44 (m, 2H), 3.08-3.25 (m, 2H), 1.99-2.22 (m, 2H); MS: [M+H]=335.

EXAMPLE 23E(3S)-N-{[2-(Methyloxy)phenyl]methyl]-N-{[2-(trifluoromethyl)phenyl]methyl}pyrrolidin-3-aminefumarate

¹H NMR (300 MHz, CD₃OD) δ_(H): 7.85-7.87 (d, 1H), 7.61-7.64 (d, 1H),7.52-7.58 (t, 1H), 7.21-7.40 (m, 3H), 6.81-6.97 (m, 2H), 6.69 (s, 2H),3.61-3.97 (m, 8H), 3.16-3.44 (m, 4H), 1.20-2.21 (m, 2H); MS: [M+H]=365.

EXAMPLE 24E(3S)-N,N-bis{[2-(Trifluoromethyl)phenyl]methyl}-pyrrolidin-3-aminefumarate

¹H NMR (300 MHz, CD₃OD) δ_(H): 7.90-7.92 (d, 2H), 7.66-7.69 (d,2H),7.59-7.64 (t, 2H), 7.40-7.45 (t, 2H), 6.69 (s, 2H), 3.91 (s, 4H),3.62-3-74 (quin, 1H), 3.36-3.46 (m, 2H), 3.16-3.26 (m, 2H), 2.02-2.24(m, 2H); MS: [M+H]=403.

The following examples illustrate compounds of of Formulae (IF) aboveand methods for their preparation.

Preparation of Intermediates

1,1-Dimethylethyl (3S)-3-aminopiperidine-1-carboxylate e)1,1-Dimethylethyl (3R)-3-hydroxypiperidine-1-carboxylate

Solid ditert-butyldicarbonate (26.6 g, 122 mmol) was added in portionsover 15 minutes to a stirred solution of (3R)-piperidin-3-olhydrochloride (15.25 g, 111 mmol), triethylamine (30.9 mL, 222 mmol) and4-(dimethylamino)-pyridine (50 mg) in dry dichloromethane (300 mL).After stirring for 18 hours at room temperature, the mixture was washedwith aqueous citric acid, then brine. The organic extracts were dried(MgSO₄), filtered and evaporated in vacuo to give an oil. This waspurified by flash chromatography on silica, eluting with ethylacetate/cyclohexane (20:80 to 80:20), to give the title compound as asolid.

f) 1,1-Dimethylethyl(3R)-3-[(methylsulfonyl)oxy]-piperidine-1-carboxylate

Methanesulfonyl chloride (9.56 mL, 124 mmol) was added dropwise over 10minutes to a stirred solution of 1,1-dimethylethyl(3R)-3-hydroxypiperidine-1-carboxylate (20.7 g, 103 mmol) andtriethylamine (21.5 mL, 154 mmol) in dichloromethane (300 mL) at 0° C.After stirring for 3 hour at 0° C., the reaction was quenched byaddition of water. The organic phase was washed with brine, dried(MgSO₄), filtered and evaporated in vacuo to give an oil. This waspurified by flash chromatography on silica, eluting with ethylacetate/cyclohexane (20:80 to 50:50), to give the title compound as anoil.

g) 1,1-Dimethylethyl (3S)-3-azidopiperidine-1-carboxylate

Sodium azide (7.65 g, 118 mmol) was added to a solution of1,1-dimethylethyl (3R)-3-[(methylsulfonyl)oxy]-piperidine-1-carboxylate(21.9 g, 78.5 mmol) in dry dimethylformamide (120 mL) and the resultantsuspension heated at 70° C. for 48 hours. After cooling to roomtemperature, the reaction mixture was diluted with water and extractedinto ethyl acetate. The organic phase was washed two further times withwater, then brine. The organic extracts were dried (MgSO₄), filtered andevaporated in vacuo to give an oil. This was purified by flashchromatography on silica, eluting with ethyl acetate/cyclohexane (10:90to 50:50), to give the title compound as an oil.

h) 1,1-Dimethylethyl (3S)-3-aminopiperidine-1-carboxylate

A mixture of 1,1-dimethylethyl (3S)-3-azidopiperidine-1-carboxylate (7.5g) and 10% palladium-on-carbon (0.75 g) in methanol (100 mL) washydrogenated in a Parr apparatus at 70 p.s.i. for 16 hours. The catalystwas removed by filtration through Celite and the solvent evaporated invacuo to give an oil. The resultant title compound was used insubsequent reactions without further purification.

2-(Bromomethyl)-4-fluoro-1,1′-biphenyl a) Methyl5-fluoro-2-{[(trifluoromethyl)sulfonyl]-oxy}benzoate

5-Fluorosalicylic acid methyl ester (28.2 g, 166 mmol) was dissolved indry dimethylformamide (165 mL) and stirred as sodium hydride (60% inoil) (7.30 g, 1.1 eq) was added portionwise over 30 mins at 0° C. Thereaction mixture was stirred for a further 30 mins at room temperature,then N-phenyl trifluoromethanesulfonimide (62.8 g, 1.05 eq) was added inportions over 30 mins, then left to stir for 3 hours. The mixture wasdiluted with diethyl ether and washed successively with water, thenbrine. The organic layers were combined, dried (MgSO₄), filtered and thesolvent removed in vacuo. The resulting oil was purified by flashchromatography on silica, eluting with ethyl acetate/cyclohexane (10:90to 40:60), to give the title compound as an oil.

b) Methyl 4-fluoro-[1,1′-biphenyl]-2-carboxylate

Palladium acetate (635 mg, 0.05 eq), tricyclohexyl-phosphine (952 mg,0.06 eq), potassium fluoride (10.85 g, 3.3 eq) and phenyl boronic acid(7.6 g, 1.1 eq) were taken up in dry THF (150 mL) and the reactionmixture flushed with nitrogen for 5 mins. A solution of methyl5-fluoro-2-{[(trifluoromethyl)sulfonyl]oxy}benzoate (17.12 g, 56.7 mmol)in THF (20 mL) was added in one portion and the reaction mixture stirredat reflux under nitrogen for 5 hours. The reaction mixture was cooled toroom temperature, diluted with ethyl acetate, then washed with water,dried (MgSO₄), filtered and the solvent removed in vacuo. The resultingoil was purified by flash chromatography on silica, eluting with ethylacetate/cyclohexane (3:97 to 10:90), to give the title compound as anoil.

c) (4-Fluoro-[1,1′-biphenyl]-2-yl)methanol

A solution of methyl 4-fluoro-[1,1′-biphenyl]-2-carboxylate (3 g, 13.1mmol) in THF (20 mL) was added at 0° C. to a suspension of lithiumaluminium hydride pellets (1 g, 26 mmol) in THF (30 mL). Upon additionthe reaction mixture was heated at 60° C. under nitrogen for 2 h. Thereaction was then cooled to 0° C. and the excess lithium aluminiumhydride destroyed by adding water, then 1N sodium hydroxide (2 mL). Themixture was extracted into diethyl ether and the organic phase was dried(MgSO₄), filtered and the solvent removed in vacuo. The resulting oilwas purified by flash chromatography on silica, eluting with ethylacetate/heptane (2:98 to 25:75), to give the title compound as an oil.

d) 2-(Bromomethyl)-4-fluoro-1,1′-biphenyl

Triphenylphosphine dibromide (35.5 g, 2 eq) was added in one portion toa solution of (4-fluoro-[1,1′-biphenyl]-2-yl)methanol (8.5 g, 42 mmol)in chloroform (250 mL). The reaction mixture was heated at 60° C. andleft to stir overnight. The solid was filtered off and the solventremoved in vacuo. The resulting oil was purified by flash chromatographyon silica, eluting with ethyl acetate/cyclohexane (0:100 to 30:70), togive the title compound as an oil.

EXAMPLE 1F(3S)-N-(2-Methylpropyl)-N-{[2-(trifluoromethyl)-phenyl]methyl}piperidin-3-amine,fumarate a) 1,1-Dimethylethyl(3S)-3-({[2-(trifluoromethyl)-phenyl]methyl}amino)piperidine-1-carboxylate

1,1-Dimethylethyl (3S)-3-aminopiperidine-1-carboxylate (1.0 g, 5 mmol),2-trifluoromethylbenzaldehyde (0.87 g, 5 mmol), 5% palladium on carbon(0.35 g) and ethanol (40 mL) were hydrogenated at 60 psi for 2.5 h.using a Parr hydrogenator. The catalyst was filtered off and thefiltrate evaporated in vacuo. The resultant oil was purified by flashchromatography on silica, eluting with ethyl acetate/cyclohexane (0:100to 75:25), to give the title compound as an oil.

b) 1,1-Dimethylethyl(3S)-3-((2-methylpropyl){[2-(trifluoromethyl)phenyl]methyl}amino)piperidine-1-carboxylate

Sodium triacetoxyborohydride (0.23 g, 1.08 mmol) was added to a stirredsolution of 1,1-dimethylethyl(3S)-3-({[2-(trifluoromethyl)phenyl]methyl}amino)piperidine-1-carboxylate(0.19 g, 0.53 mmol), isobutyraldehyde (0.12 g, 1.6 mmol)and1,2-dichloroethane (5 mL). After stirring under nitrogen at roomtemperature for 1 day, the reaction mixture was diluted with methanol (6mL) and absorbed onto a cationic ion exchange resin (Isolute™ SCX-2).After washing the cartridge with methanol (25mL), the basic componentswere isolated by elution with 2N ammonia in methanol and the eluateevaporated to give an oil.

c)(3S)-N-(2-Methylpropyl)-N-{[2-(trifluoromethyl)-phenyl]methyl}piperidin-3-amine,fumarate

1,1-Dimethylethyl(3S)-3-((2-methylpropyl){[2-(trifluoromethyl)phenyl]methyl}amino)piperidine-1-carboxylate(0.139 mg, 0.335 mmol), trifluoroacetic acid (4 mL) and dichloromethane(10 mL) were stirred at room temperature for 1 day. The solution wasevaporated in vacuo to give an oil, which was redissolved in methanoland filtered through a cationic ion exchange resin (Isolute™ SCX-2). Thebasic components were isolated by elution with 2N ammonia in methanol.The eluate was evaporated in vacuo and the resultant oil converted tothe fumaric acid salt (crystallisation from ethanol/ether), to give thetitle compound as a white solid. ¹H NMR (300 MHz, CD₃OD): δ_(H)7.77-7.74 (d, H), 7.51-7.43 (m, 2H), 7.25-7.22 (t, 1H), 4.23 (s, 2H)3.79-3.66 (q, 2H), 3.21-3.08 (m, 4H), 2.83-2.61 (m, 3H), 2.28-2.10 (m,2H), 1.90-1.82 (m, 2H), 1.59-1.37 (m, 3H), 0.77-72 (t, 6H); MS:(M+H)=315.

The following Examples were similarly prepared as described above forExample 1F, by reductive alkylation of 1,1-dimethylethyl(3S)-3-({[2-(trifluoromethyl)-phenyl]methyl}amino)piperidine-1-carboxylatewith the appropriate aldehyde or ketone, and subsequent deprotection:

EXAMPLE 2F(3S)-N-(3,3-Dimethylbutyl)-N-{[2-(trifluoromethyl)-phenyl]methyl}piperidin-3-amine,D-tartrate

¹HNMR (300 MHz, CD₃OD): δ_(H) 7.79-7.86 (d, 1H), 7.47-7.56 (m, 2H),7.27-7.32 (t, 2H), 4.30 (s, 2H), 3.73-3.84 (t, 2H), 3.16-3.28 (m, 2H),2.71-2.89 (m, 3H), 2.47-2.52 (t, 2H), 1.84-1.97 (m, 2H), 1.47-1.63 (m,2H), 1.22-1.33 (m, 2H), 0.75 (s, 9H); MS: [M+H]=343.

EXAMPLE 3F(3S)-N-Cyclohexyl-N-{[2-(trifluoromethyl)phenyl]-methyl}piperidin-3-amine,D-tartrate

¹HNMR (300 MHz, CD₃OD): δ_(H) 7.88-7.91 (d, 1H), 7.51-7.58 (m, 2H),7.29-7.34 (t, 1H), 4.29 (s, 2H), 3.68-3.83 (q, 2H), 3.43-3.50 (m, 1H),3.08-3.27 (m, 1H), 2.87-3.00 (m, 2H), 2.39-2.45 (dd, 1H), 2.22-2.29 (dd,1H), 2.22-2.16 (m, 2H), 1.76-1.90 (m, 2H), 1.58-1.62 (m, 1H), 1.27-1.41(m, 2H), 1.08-1.22 (m, 2H), 0.97-1.03 (1H), 0.63-0.74 (m, 4H); MS:[M+H]=341.

EXAMPLE 4F(3S)-N-{[5-Fluoro-2-(trifluoromethyl)phenyl]methyl}-N-tetrahydro-2H-pyran-4-ylpiperidin-3-amine,L-tartrate a) 1,1-Dimethylethyl(3S)-3-(tetrahydro-2H-pyran-4-ylamino)piperidine-1-carboxylate

1,1-Dimethylethyl-(3S)-3-aminopiperidine-1-carboxylate (2 g, 11 mmol),4H-tetrahydropyran-4-one (1.1 g, 11 mmol) and dichloroethane (40 mL)were stirred under nitrogen at room temperature for 15 min. Sodiumtriacetoxyborohydride (2.9 g, 14 mmol) was added in 3 lots over 30minutes and stirred overnight. The reaction was diluted with water (50mL) and made basic by addition of 2N NaOH solution. After stirring for 1h, the mixture was extracted into dichloromethane, and the combinedorganic extracts washed with brine, dried (MgSO₄), filtered andevaporated in vacuo to give the title compound as an oil.

b)(3S)-N-{[5-Fluoro-2-(trifluoromethyl)phenyl]methyl}-N-tetrahydro-2H-pyran-4-ylpiperidin-3-amine,L-tartrate

1,1-Dimethylethyl(3S)-3-(tetrahydro-2H-pyran-4-ylamino)piperidine-1-carboxylate wasreductively alkylated with 5-fluoro-2-(trifluoromethyl)benzaldehyde,then deprotected and crystallised as its L-tartrate salt as describedabove for Example 1 b) and c), to give the title compound. ¹HNMR (300MHz, CD₃OD): δ_(H) 7.74-7.75 (m, 2H), 7.05-6.98 (t, 1H), 4.50 (s, 2H),3.99-3.85 (m, 4H), 3.43-2.58 (m, 8H), 2.02-1.42 (m, 8H); MS: [M+H]=361.

The following Examples were similarly prepared as described above forExample 4F, by reductive alkylation of 1,1-dimethylethyl(3S)-3-(tetrahydro-2H-pyran-4-ylamino)-piperidine-1-carboxylate with theappropriate benzaldehyde, and subsequent deprotection:

EXAMPLE 5F(3S)-N-[(2-Chloro-5-fluorophenyl)methyl]-N-tetrahydro-2H-pyran-4-ylpiperidin-3-amine,L-tartrate

¹HNMR (300 MHz, CD₃OD): δ_(H) 7.32-7.24 (m, 2H), 6.92-6.85 (t, 1H), 4.30(s, 2H), 3.90-3.84 (m, 4H), 3.32-3.17 (m, 4H), 3.08-2.97 (m, 1H),2.85-2.67 (m, 3H), 1.98-1.82 (m, 2H), 1.73-1.82 (m,2H), 1.73-1.46 (m,6H); MS: [M+H]=327/329.

EXAMPLE 6F(3S)-N-([1,1′-Biphenyl]-2-ylmethyl)-N-tetrahydro-2H-pyran-4-ylpiperidin-3-amine,sesqui-L-tartrate

¹HNMR (300 MHz, CD₃OD): δ_(H) 7.51-7.48 (d, 1H), 7.35-7.17 (m, 7H),7.08-7.05 (d, 1H), 3.30 (s, 1.5H), 3.79-3.74 (dd, 2H), 3.69 (s, 2H),3.25-3.10 (m, 9H), 3.20-3.09 (m, 2H), 2.91-2.77 (m, 2H), 2.66-2.51 (m,3H); MS: [M+H]=351.

EXAMPLE 7F(3S)-N-[(2-Chlorophenyl)methyl]-N-tetrahydro-2H-pyran-4-ylpiperidin-3-amine,D-tartrate

¹HNMR (300 MHz, CD₃OD): δ_(H) 7.52-7.49 (d, 1H), 7.26-7.87 (m, 3H), 4.30(s, 2H), 3.92-3.80 (m, 4H), 3.16-2.34 (m, 4H), 2.92-2.05 (m, 1H),2.90-2.66 (m, 3H), 1.93-187 (m, 2H), 1.68-1.39 (m, 6H); MS:[M+H]=309/311.

EXAMPLE 8F(3S)-N-Tetrahydro-2H-pyran-4-yl-N-{[2-(trifluoromethyl)phenyl]methyl}piperidin-3-amine,D-tartrate

¹HNMR (300 MHz, CD₃OD): δ_(H) 7.98-7.95 (d, 1H), 7.71-7.62 (q, 2H),7.47-7.42 (t, 1H), 4.44 (s, 2H), 4.14-3.98 (m, 4H), 3.43-3.29 (m, 4H),3.11-2.82 (m, 4H), 2.06-2.03 (m, 2H), 1.82-1.66 (m, 6H); MS: [M+H]=343.

EXAMPLE 9F(3S)-N-Cyclopentyl-N-{[2-(trifluoromethyl)phenyl]-methyl}piperidin-3-amine,L-tartrate a) 1,1-Dimethylethyl(3S)-3-(cyclopentylamino)-piperidine-1-carboxylate

1,1-Dimethylethyl (3S)-3-aminopiperidine-1-carboxylate (2.1 g, 10.5mmol), cyclopentanone (4.65 mL, 52.5 mmol), and 10% palladium on carbon(0.2 g) in methanol (80 mL) were hydrogenated at 60 psi overnight in aParr hydrogenator. The catalyst was filtered off and the filtrateevaporated in vacuo. The resultant oil was purified by flashchromatography on silica, eluting with ethyl acetate/cyclohexane (15:85to 30:70), to give the title compound as an oil.

b) 1,1-Dimethylethyl(3S)-3-(cyclopentyl{[2-(trifluoromethyl)phenyl]methyl}amino)piperidine-1-carboxylate

1,1-Dimethylethyl (3S)-3-(cyclopentylamino)-piperidine-1-carboxylate(155 mg, 0.577 mmol), 2-(trifluoromethyl)benzyl bromide (0.105 mL, 1.2eq) and anhydrous potassium carbonate (128 mg, 1.6 eq) in acetonitrile(3 mL) were heated at refluxed under nitrogen for 2 days. The reactionmixture was cooled to room temperature, diluted with ethyl acetate andwashed with water, then brine. The organic extracts were dried (MgSO₄),filtered and evaporated in vacuo. The resulting oil was purified byflash chromatography on silica eluting with ethyl acetate/cyclohexane(0:100 to 30:70), to give the title compound as an oil.

c)(3S)-N-Cyclopentyl-N-{[2-(trifluoromethyl)phenyl]-methyl}piperidin-3-amine,L-tartrate

1,1-Dimethylethyl(3S)-3-(cyclopentyl{[2-(trifluoromethyl)phenyl]methyl}amino)piperidine-1-carboxylate(160 mg, 0.38 mmol), trifluoroacetic acid (0.5 mL) and dichloromethane(2 mL) were stirred at room temperature overnight. The solution wasevaporated in vacuo to give an oil, which was redissolved in methanoland filtered through a cationic ion exchange resin (Isolute™ SCX-2). Thebasic components were isolated by elution with 2N ammonia in methanol.The eluate was evaporated in vacuo and the resultant oil converted tothe L-tartaric acid salt (freeze drying from acetonitrile/water 1: 1),to give the title compound as a white solid. ¹H NMR (300 MHz, CD₃OD):δ_(H) 7.89-7.86 (d, 1H), 7.54-7.46 (m, 2H), 7.30-7.25 (t, 1H), 4.34 (s,2H), 3.90-3.78 (q, 2H), 3.30-3.18 (m, 4H), 3.05-2.87 (m, 1H), 2.81-2.59(m, 2H), 1.95-1.79 (m, 2H), 1.68-1.30 (m, 9H); MS: [M+H]=327.

The following Examples were similarly prepared as described above forExample 9F, by reaction of 1,1-dimethylethyl(3R)-3-(cyclopentylamino)piperidine-1-carboxylate with the appropriatebenzyl bromide and subsequent deprotection:

EXAMPLE 10F(3S)-N-([1,1′-Biphenyl]-2-ylmethyl)-N-cyclopentyl-piperidin-3-amine,L-tartrate

¹H NMR (300 MHz, CD₃OD): δ_(H) 7.57-7.55 (d, 1H), 7.35-7.13 (m, 7H),7.06-7.03 (d, 1H), 4.30 (s, 2H), 3.58 (s, 2H), 3.12-2.98 (m, 3H),2.82-2.73 (m, 1H), 2.65-2.42 (m, 2H), 1.79-1.75(m, 1H), 1.69-1.65 (m,1H), 1.53-1.19(m, 10H); MS: [M+H]=335.

EXAMPLE 11F(3S)-N-Cyclopentyl-N-([5-fluoro-1,1′-biphenyl]-2-ylmethyl)-piperidin-3-amine,L-tartrate

¹H NMR (300 MHz, CD₃OD): δ_(H) 7.35-7.24 (m, 4H), 7.18-7.15 (m, 2H),7.09-7.04 (m, 1H), 6.92-6.85 (m, 1H), 4.28 (s, 2H), 3.55 (m, 2H),3.22-3.06 (m, 3H), 2.82-2.77 (m, 1H), 2.68-2.58 (m, 2H), 1.88-1.68 (m,2H), 1.57-1.19 (m, 10H); MS: [M+H]=353.

EXAMPLE 12 F(3S)-N-(Tetrahydrofuran-3-ylmethyl)-N-{[2-(trifluoromethyl)phenyl]methyl}piperidin-3-amine,L-tartrate a) 1,1-Dimethylethyl(3S)-3-[(tetrahydrofuran-3-ylmethyl)amino]piperidine-1-carboxylate

To 5% palladium on carbon (0.05 g) under nitrogen was added a solutionof 1,1-dimethylethyl-(3S)-3-aminopiperidine-1-carboxylate (0.50 g, 2.5mmol) and tetrahydrofuran-3-carboxaldehyde (50% w/w in water) (0.50 g,2.5 mmol) in ethanol (20 mL). The reaction mixture was hydrogenatedovernight at 60 psi in a Parr hydrogenator. The catalyst was removed byfiltration through Celite and the solvent removed in vacuo to give1,1-dimethylethyl(3S)-3-[(tetrahydrofuran-3-ylmethyl)amino]piperidine-1-carboxylate as acolourless, slightly cloudy oil.

b)(3S)-N-(Tetrahydrofuran-3-ylmethyl)-N-{[2-(trifluoromethyl)phenyl]methyl}piperidin-3-amine,L-tartrate

To a solution of 1,1-dimethylethyl(3S)-3-[(tetrahydrofuran-3-ylmethyl)amino]piperidine-1-carboxylate (0.67g, 2.36 mmol) in 1,2-dichloroethane (15 mL) was added2-(trifluoromethyl)benzaldehyde (0.93 mL, 7.07 mmol). To this mixturewas added a solution of sodium triacetoxyborohydride (1.50 g, 7.07 mmol)in dimethylformamide (3 mL) and left to stir under nitrogen, at roomtemperature, over the weekend. To the reaction mixture was added water(10 mL) and the solution stirred vigorously for several minutes. Thechlorinated organic layer was absorbed directly onto a silica column andthe product eluted with methanol/ethyl acetate (0:100 to 30:70). Theresultant pale yellow oil was taken up in methanol and absorbed onto acationic ion exchange resin (Isolute™ SCX-2). After washing thecartridge with methanol (25 mL), the basic components were isolated byelution with 2N ammonia in methanol and the eluate evaporated to give1,1-dimethylethyl(3S)-3-{(tetrahydrofuran-3-ylmethyl){[2-(trifluoromethyl)-phenyl]methyl}amino}piperidine-1-carboxylateas a colourless oil.

To a solution of this oil (0.82 g, 1.85 mmol) in dichloromethane (10 mL)was added trifluoroacetic acid (2.06 mL, 27.8 mmol). The reactionmixture was stirred overnight at room temperature, then the solventremoved in vacuo. The resulting oil was taken up in methanol andabsorbed onto a cationic ion exchange resin (Isolute™ SCX-2). Afterwashing the cartridge with methanol (50 mL), the basic components wereisolated by elution with 2N ammonia in methanol. The eluate wasevaporated in vacuo to give a colourless oil. The diastereomers wereseparated by hplc (Chiralpak AD-H column; 98% heptane, 2% ethanol and0.2% diethylamine). The faster eluting isomer was taken up in methanoland to this was added a solution of L-tartaric acid (0.046 g, 0.31 mmol)in methanol. Solvent was removed in vacuo and the resulting oiltriturated with diethyl ether. Filtration of the resultant suspensiongave the title compound as a white solid.

¹HNMR (300 MHz, CD₃OD): δ_(H) 7.75 (1H, d), 7.58-7.50 (2H, m), 7.34-7.29(1H, m), 4.30 (3H, s), 3.83 (2H, s), 3.70-3.53 (3H, m), 3.42-3.31 (2H,m), 3.16 (1H, m) 2.90-2.67 (3H, m), 2.54-2.34 (2H, m), 2.34-2.20 (1H,m), 1.95-1.84 (3H, m), 1.63-1.45 (3H, m); MS: [M+H]=343.

The following Examples were prepared from racemic 1,1-dimethylethyl3-aminopiperidine-1-carboxylate, as described above in Example 1F:

EXAMPLE 13FN-{[2-(Methyloxy)phenyl]methyl}-N-{[2-(trifluoromethyl)phenyl]methyl}piperidin-3-amine

¹HNMR (300 MHz, CDCl₃) δ_(H) 8.04-7.95 (d, 1H), 7.57-7.54 (d, 1H),7.48-7.44 (m, 2H), 7.28-7.11 (m, 2H), 6.93-6.88 (t, 1H), 6.83-6.80 (d,1H), 3.94-3.86 (d, 2H), 3.20-3.18 (d, 1H), 2.94-2.90 (d, 1H), 2.68-2.55(m, 2H), 2.49-2.40 (dt, 1H), 2.08-2.04 (d, 1H), 1.76-1.72 (d, 1H),1.52-1.25 (m, 4H); MS: [M+H]=379.

EXAMPLE 14FN-Cyclohexyl-N-{[2-(trifluoromethyl)phenyl]methyl}-piperidin-3-amine

¹HNMR (300 MHz, CDCl₃) δ_(H) 8.01-7.93 (d, 1H), 7.59-7.56 (d, 1H),7.51-7.46 (t, 1H), 7.30-7.19 (m, 1H), 3.91 (s, 2H), 3.15-3.11 (d, 1H),3.02-2.98 (d, 1H), 2.88-2.80 (d, 1H), 2.55-2.41 (m, 3H), 1.93-1.01 (m,14); MS: [M+H]=341.

EXAMPLE 15FN-(Phenylmethyl)-N-{[2-(trifluoromethyl)phenyl]-methyl}piperidin-3-amine

¹HNMR (300 MHz, CDCl₃) δ_(H) 7.93-7.96 (d, 1H), 7.55-7.61 (d, 1H),7.47-7.51 (t, 1H), 7.18-7.35 (m, 6H), 3.77-3.90 (q, 2H), 3.64-3.74 (q,2H), 3.17-3.20 (d, 1H), 2.91-2.95 (d, 1H), 2.53-2.67 (m, 2H), 2.39-2.48(dt, 1H), 1.97-2.06 (d, 1H), 1.22-1.82 (m,3H); MS: [M+H]=349.

EXAMPLE 16F(3S)-N-(2-Methylpropyl)-N-{[2-(trifluoromethyl)phenyl]-methyl}-1-azabicyclo[2.2.2]octan-3-amine,sesquifumarate a)(3S)-N-{[2-(Trifluoromethyl)phenyl]methyl}-1-azabicyclo[2.2.2]octan-3-amine

Sodium triacetoxyborohydride (18.7 g, 88.3 mmol) was added portionwiseover 20 min. to a stirred solution of(3S)-1-azabicyclo[2.2.2]octan-3-amine dihydrochloride (5 g, 25.1 mmol)and 2-trifluoromethylbenzaldehyde (4.81 g, 27.6 mmol) in DMF (100 mL).After stirring under nitrogen for 4 days, the mixture was diluted withexcess water, basified with 2N sodium hydroxide and stirred for 1 h. Theproduct was extracted into dichloromethane and evaporated in vacuo togive an oil, which was dissolved in 2N hydrochloric acid. After washingwith ether, the aqueous phase was basified with 2N sodium hydroxide andextracted with dichloromethane. The organic phase was dried (MgSO₄) andevaporated in vacuo to give an oil. ¹HNMR (300 MHz, CD₃OD) δ_(H):7.62-7.69 (t, 2H), 7.50-7.55 (t, 1H), 7.32-7.37 (t, 1H), 3.83-3.96 (q,2H), 3.1-3.19 (m, 1H), 2.72-2.93 (m, 5H), 2.42-2.49 (m, 1H), 1.85-1.95(m, 1H), 1.63-1.73 (m, 1H), 1.32-1.53); MS: [M+H]=285.

b)(3S)-N-(2-Methylpropyl)-N-{[2-(trifluoromethyl)-phenyl]methyl)-1-azabicyclo[2.2.2]octan-3-amine,sesquifumarate

(3S)-N-{[2-(Trifluoromethyl)phenyl]methyl}-1-azabicyclo[2.2.2]octan-3-amine(0.30 g, 1.06 mmol), isobutyraldehyde (0.152 g, 2.1 mmol) and1,2-dichloroethane (6 mL) were stirred under nitrogen at roomtemperature for 15 min. Sodium triacetoxyborohydride (0.492 g, 2.32mmol) was added in two lots over 5 min. TLC after 1 day showed thereaction to be incomplete, so additional sodium triacetoxyborohydride(0.24 g, 1.15 mmol) was added and the mixture heated at 50° C. for 5days. After cooling to room temperature, methanol was added and themixture was stirred for 1 h. This solution was filtered through acationic ion exchange resin (Isolute™ SCX-2) and the basic fractionsisolated by elution with 2N ammonia in methanol to give, afterevaporation in vacuo, an oil. The crude product was purified usingpreparative LCMS to give the product as an acetate salt, which wasconverted to the free base using cationic ion exchange resin asdescribed above. The free base was converted to the fumarate salt, togive the title compound as a white solid from ethanol/diethyl ether.¹HNMR (300 MHz, CD₃OD) δ_(H): 7.88-7.91 (d, 1H), 7.51-7.58 (m, H),7.30-7.35 (t, 1H), 6.60 (s, 3H), 3.71-3.85 (q, 2H), 3.42-4.50 (m, 1H),2.88-3.26 (m, 6H), 2.25-2.39 (m, 1H), 2.09-2.23 (m, 3H), 1.74-1.91 (m,2H), 1.42-1.63 (m, 2H), 0.78-0.83 (t, 6H); MS: [M+H]=341.

The following Examples were similarly prepared as described above forExample 16F, from(3S)-N-{[2-(trifluoromethyl)phenyl]methyl}-1-azabicyclo-[2.2.2]octan-3-amineand the appropriate substituted benzaldehyde:

EXAMPLE 17F(3S)-N-([1,1′-Biphenyl]-2-ylmethyl)-N-(2-methylpropyl)-1-azabicyclo[2.2.2]octan-3-amine,D-tartrate

¹HNMR (300 MHz, CD₃OD) δ_(H): 7.50-7.47 (d, 1H), 7.38-7.18 (m, 7H),7.09-7.06 (dd, 1H), 4.29 (s, 2H), 3.58-3.54 (d, 1H), 3.43-3.39 (d,1H),3.25-3.18 (m, 1H), 3.09-3.90 (4H), 2.68-2.63 (t,1H), 2.45-2.39 (dq, 1H),2.16-1.98 (m, 3H), 1.83-1.74 (m, 2H), 1.65-1.61 (m, 1H), 1.45-1.42 (m,1H), 1.31-1.22 (quin, 1H), 0.65-0.61 (t, 6H); MS: [M+H]=349.

EXAMPLE 18F(3S)-N-{[4-Fluoro-2-(trifluoromethyl)phenyl]methyl}-N-(2-methylpropyl)-1-azabicyclo[2.2.2]octan-3-amine,L-tartrate

¹HNMR (300 MHz, CD₃OD) δ_(H): 7.94-7.89 (t, 1H), 7.34-7.27 (m, 2H), 4.29(s, 4.29), 3.81-3.66 (q, 2H), 3.51-3.44 (t,1H), 3.40-2.89 (m, 6H),2.37-2.04 (m, 4H), 1.93-1.38 (m, 4H), 0.82-0.76 (dd, 6H); MS: [M+H]=359.

EXAMPLE 19F(3S)-N-1(4-Fluoro[1,1′-biphenyl]-2-yl)methyl]-N-(2-methylpropyl)-1-azabicyclo[2.2.2]octan-3-amine,L-tartrate

¹HNMR (300 MHz, CD₃OD) δ_(H): 7.40-7.08 (m, 7H). 6.68-6.91 (dt, 1H),4.29 (s, 2H), 3.56-4.0 (q, 2H), 3.31-2.96 (m, 5H), 2.72-2.67 (t, 1H),2.58-2.52 (dq, 1H), 2.18-1.30 (m, 8H), 0.70-0.68 (dd, 6H); MS:[M+H]=367.

The following examples illustrate compounds of of Formulae (IG) aboveand methods for their preparation.

Preparation of Intermediates

(2S)-(4-Benzyl-morpholin-2-yl)-phenyl-methanone

Described above in section entitled “Preparation of intermediates forthe synthesis of Examples 1C-17C”.

(S)-Phenyl[(2S)-4-(phenylmethyl)morpholin-2-yl]methanol (2)

Described above in section entitled “Preparation of intermediates forthe synthesis of Examples 1C-17C”.

(2S)-2-[(R)-bromo(phenyl)methyl]-4-(phenylmethyl)morpholine (3)

To a solution of (S)-phenyl[(2S)-4-(phenylmethyl)morpholin-2-yl]methanol(2) (4.71 g, 16.63 mmole) in chloroform (200 ml) is added thetriphenylphosphine dibromide (14.04 g, 33.26 mmole). The mixture isheated at 60° C. overnight. The mixture is allowed to cool to roomtemperature then washed with saturated sodium carbonate solution(aqueous, ˜100 ml), dried (Na₂SO₄) and concentrated in vacuo. Theresulting residue is purified by automated flash chromatography (ISCOsystem: 120 g column, 10-30% EtOAc in isohexane) to give(2S)-2-[(R)-bromo(phenyl)methyl]-4-(phenylmethyl)morpholine (3) as awhite solid (4.63 g, 80%). LCMS 6 min gradient method, Rt=2.5 min,(M+H⁺)=346/348

S-{(S)-phenyl[(2S)-4-(phenylmethyl)morpholin-2-yl]methyl}ethanethioate(5)

A solution of(2S)-2-[(R)-bromo(phenyl)methyl]-4-(phenylmethyl)morpholine (3) (1.76 g,5.08 mmole) and potassium thiolacetate (1.16 g, 10.16 mmole) in 1:1anhydrous THF:DMF (30 ml), is stirred at 40° C. under nitrogenovernight. The mixture is then taken up in acetonitrile and loaded ontoan SC10-2 column (4×10 g). The SC10-2 columns are washed with furtheracetonitrile. The target compound is eluted with 4:1 acetonitrile: Et₃N.This is concentrated in vacuo to give an orange oil which is purified byautomated flash chromatography (ISCO system: 35 g SiO₂ Redisep column,10-30% EtOAc in isohexane over 40 minutes) to giveS-{(S)-phenyl[(2S)-4-(phenylmethyl)morpholin-2-yl]methyl}ethanethioate(5) as an amber coloured crystalline solid (1.54 g, 89%). LCMS 6 mingradient method, Rt=2.5 min, (M+H⁺)=342

(S)-phenyl[(2S)-4-(phenylmethyl)morpholin-2-yl]methanethiol (6)

TheS-{(S)-phenyl[(2S)-4-(phenylmethyl)morpholin-2-yl]methyl}ethanethioate(5) (11.02 g, 32.3 mmole) is taken up in methanol (100 ml, dry,degassed), under nitrogen. To this is added the sodium thiomethoxide(2.26 g, 32.3 mmole) in one portion (as solid). The reaction mixture isleft to stir at room temperature for 2 hours. The solution is then addedto an aqueous solution of HCl (0.1 M). This is extracted with DCM (3×).The extracts are dried (Na₂SO₄) and concentrated in vacuo to give(S)-phenyl[(2S)-4-(phenylmethyl)morpholin-2-yl]methanethiol (6) as ayellow solid (9.59 g, 99%). LCMS 6 min gradient method, Rt=2.7 min,(M+H⁺)=300

EXAMPLES Example 1G(2S)-2-{(S)-phenyl[(3-phenylpyridin-2-yl)thio]methyl}morpholinehemifumarate

i) To palladium acetate (0.026 g, 0.12 mmole) in acetonitrile (3 ml), isadded triphenylphosphine (0.122 g, 0.46 mmole), under nitrogen, at roomtemperature. The mixture is left to stir for 15 minutes. To this mixtureis added water (distilled, 1 ml), phenylboronic acid (0.846 g, 6.94mmole), 3-bromo-2-fluoropyridine (1.02 g, 5.78 mmole) and potassiumcarbonate (4.80 g, 34.70 mmole). The reaction mixture is heated at 70°C. overnight. After cooling to room temperature, the reaction mixture isloaded directly onto a 40 g Redisep SiO₂ column and components isolatedby automated flash chromatography (ISCO System, 0-30% ethyl acetate incyclohexane gradient elution over 40 minutes). This gave2-fluoro-3-phenylpyridine as a very pale yellow oil (1.00 g, 100%). LCMS6 min gradient method, Rt=3.7 min, (M+H⁺)=174.

ii) To a solution of(S)-phenyl[(2S)-4-(phenylmethyl)morpholin-2-yl]methanethiol (6) (1.50 g,5.01 mmole) and 2-fluoro-3-phenylpyridine (2.44 g, 14.09 mmole) in dry,degassed DMF (10 ml) is added, under nitrogen, sodium hydride (60%dispersion in oil, 0.24 g, 6.01 mmole). The mixture is left to stirovernight at room temperature. The reaction mixture is loaded neat ontoa 120 g SiO₂ Redisep column (preconditioned with cyclohexane). Automatedflash chromatography (ISCO System, 0-30% ethyl acetate in cyclohexanegradient elution over 40 minutes at 40 ml/minute flow rate) yielded anorange oil (2.26 g). Chromatography is repeated using chromatography(ISCO System, 40 g column, 0-30% ethyl acetate in cyclohexane gradientelution over 40 minutes at 30 ml/minute flow rate) to give(2S)-2-{(S)-phenyl[(3-phenylpyridin-2-yl)thio]methyl}-4-(phenylmethyl)morpholineas a pale orange oil (1.65 g, 73%). LCMS 6 min gradient method, Rt=4.0min, (M+H⁺)=453.

iii) To a suspension of polymer supported diisopropylamine (3.78 mmol/g,0.54 g, 2.03 mmole) and(2S)-2-{(S)-phenyl[(3-phenylpyridin-2-yl)thio]methyl}-4-(phenylmethyl)morpholine(0.184 g, 0.41 mmole) in dry DCM (5 ml) is added 1-chloroethylchloroformate (0.22 ml, 2.03 mmole) at room temperature and undernitrogen. The mixture is heated at 40° C. for 3.75 hours. The reactionmixture is filtered, concentrated in vacuo then taken up in methanol (5ml). The solution is left to stir at room temperature overnight. Afterthis time, the reaction mixture is loaded directly onto an SC10-2column. The SC10-2 column is washed with methanol. The title compound iseluted with 2 N NH₃/methanol. This is concentrated in vacuo to give(2S)-2-{(S)-phenyl[(3-phenylpyridin-2-yl)thio]methyl}morpholine as whitefoam (0.148 g, 100%). The foam is taken up in ethyl acetate. To this isadded a solution of fumaric acid (1.1 equiv, 0.052 g) in methanol. Theresulting solution is filtered then concentrated in vacuo. To theresulting white solid is added methanol (1.5 ml). This is stirred for acouple of minutes, then the remaining solid collected by filtration togive the hemi-fumarate salt of(2S)-2-{(S)-phenyl[(3-phenylpyridin-2-yl)thio]methyl}morpholine as awhite solid (0.127 g). LCMS 12 min gradient method, Rt=5.5 min,(M+H⁺)=363

Example 2G(2S)-2-[(S)-{[3-(4-fluorophenyl)pyridin-2-yl]thio}(phenyl)methyl]morpholinefumarate

i) To bis(benzonitrile)palladium(II)dichloride (0.054 g, 0.14 mmole) and1,4-bis(diphenylphosphine)butane (0.091 g, 0.21 mmole) is added drytoluene (6 ml), under nitrogen, and the mixture stirred for half anhour. To this is added 3-bromo-2-fluoropyridine (0.50 g, 2.83 mmole) inethanol (1.4 ml) followed by a solution of 4-fluorophenylboronic acid(0.793 g, 5.67 mmole) in ethanol (2.4 ml). To this is added an aqueoussolution of sodium carbonate (1 M, 2.83 ml, 2.83 mmole). The mixture isheated at 60° C. for 24 hours, then at 75° C. for a further 16 hours.The organic layer is loaded directly onto a 40 g Redisep SiO₂ column andcomponents isolated by automated flash chromatography (ISCO System,0-30% ethyl acetate in cyclohexane gradient elution over 40 minutes).This gave 3-(4-fluorophenyl)-2-fluoropyridine as a white solid (0.387 g,71%). LCMS 6 min gradient method, Rt=3.6 min, (M+H⁺)=192

ii) To a solution of(S)-phenyl[(2S)-4-(phenylmethyl)morpholin-2-yl]methanethiol (6) (0.505g, 1.69 mmole) and 3-(4-fluorophenyl)-2-fluoropyridine (0.387 g, 2.02mmole) in dry, degassed DMF (3 ml) is added, under nitrogen, cesiumfluoride (0.385 g, 2.54 mmole). The mixture is heated at 65° C. over theweekend. After this time, the reaction mixture is allowed to cool andloaded directly onto an SC10-2 column. The SC10-2 column is washed withmethanol. The(2S)-2-[(S)-{[3-(4-fluorophenyl)pyridin-2-yl]thio}(phenyl)methyl]-4-(phenylmethyl)morpholineis eluted with 2 N NH₃/methanol. This is concentrated in vacuo to givean orange solid (0.649 g). This is purified by automated flashchromatography (ISCO System, 40 g SiO₂ Redisep column, 0-30% ethylacetate in cyclohexane gradient elution over 40 minutes at 30 ml/minuteflow rate) to give(2S)-2-[(S)-{[3-(4-fluorophenyl)pyridin-2-yl]thio}(phenyl)methyl]-4-(phenylmethyl)morpholineas a off-white foam (0.395 g, 50%). LCMS 6 min gradient method, Rt=3.3min, (M+H⁺)=471.

iii) Deprotection of the morpholine nitrogen is carried out using themethod and work up as described in Example 1G, using polymer supporteddiisopropylamine (3.78 mmole/g, 1.09 g, 4.14 mmole),(2S)-2-[(S)-{[3-(4-fluorophenyl)pyridin-2-yl)thio}(phenyl)methyl]-4-(phenylmethyl)morpholine(0.390 g, 0.83 mmole), dry DCM (20 ml), 1-chloroethyl chloroformate(0.45 ml, 4.14 mmole) and methanol (20 ml). This gave(2S)-2-[(S)-{[3-(4-fluorophenyl)pyridin-2-yl]thio}(phenyl)methyl]morpholineas a pale yellow oil (0.232 g, 74%). This oil is taken up in ethylacetate. To this is added a solution of fumaric acid (1.1 equiv, 0.071g) in methanol. The resulting solid is collected by filtration to give awhite solid (0.115 g). This is recrystallised from MeOH/CHCl₃/Et₂O togive a white solid (0.061 g). LCMS 12 min gradient method, Rt=5.4 min,(M+H⁺)=381

Example 3G(2S)-2-[(S)-{[3-(3-chlorophenyl)pyridin-2-yl]thio}(phenyl)methyl]morpholinefumarate

i) To bis(benzonitrile)palladium(II)dichloride (0.054 g, 0.14 mmole) and1,4-bis(diphenylphosphine)butane (0.091 g, 0.21 mmole) is added drytoluene (6 ml), under nitrogen, and the mixture stirred for half anhour. To this is added 3-bromo-2-fluoropyridine (0.50 g, 2.83 mmole) inethanol (1.4 ml) followed by a solution of 3-chlorophenylboronic acid(0.887 g, 5.67 mmole) in ethanol (2.4 ml). To this is added an aqueoussolution of sodium carbonate (1 M, 2.83 ml, 2.83 mmole). The mixture isheated at 60° C. for 24 hours, then at 75° C. for a further 16 hours.The organic layer is loaded directly onto a 40 g Redisep SiO₂ column andcomponents isolated by automated flash chromatography (ISCO System,0-30% ethyl acetate in cyclohexane gradient elution over 40 minutes).This gave 3-(3-chlorophenyl)-2-fluoropyridine as an off-white solid(0.333 g, 57%). LCMS 6 min gradient method, Rt=4.0 min, (M+H⁺)=208.

ii) To a solution of(S)-phenyl[(2S)-4-(phenylmethyl)morpholin-2-yl]methanethiol (6) (0.400g, 1.34 mmole) and 3-(3-chlorophenyl)-2-fluoropyridine (0.333 g, 1.60mmole) in dry, degassed DMF (3 ml) is added, under nitrogen, cesiumfluoride (0.305 g, 2.00 mmole). The mixture is heated at 65° C. over theweekend. After this time, the reaction mixture allowed to cool. Theresulting solid is taken up in MeOH/DCM and loaded directly onto anSC10-2 column. The SC10-2 column is washed with methanol. The(2S)-2-[(S)-{[3-(3-chlorophenyl)pyridin-2-yl]thio}(phenyl)methyl]-4-(phenylmethyl)morpholineis eluted with 2 N NH₃/methanol. This is concentrated in vacuo to give awhite foam (0.555 g). This is purified by automated flash chromatography(ISCO System, 0-30% ethyl acetate in cyclohexane gradient elution over40 minutes at 40 ml/minute flow rate) to yield(2S)-2-[(S)-{[3-(3-chlorophenyl)pyridin-2-yl]thio}(phenyl)methyl]-4-(phenylmethyl)morpholineas a white foam (0.258 g, 40%). LCMS 6 min gradient method, Rt=4.2 min,(M+H⁺)=487.

iii) Deprotection of the morpholine nitrogen is carried out using themethod and work up as described in Example 1G, using polymer supporteddiisopropylamine (3.72 mmole/g, 0.70 g, 1.80 mmole),(2S)-2-[(S)-{[3-(3-chlorophenyl)pyridin-2-yl]thio}(phenyl)methyl]-4-(phenylmethyl)morpholine(0.255 g, 0.52 mmole), dry DCM (15 ml), 1-chloroethyl chloroformate(0.29 ml, 2.62 mmole) and methanol (15 ml). This gave a colourlessresidue (0.211 g). This residue is taken up in ethyl acetate. To this isadded a solution of fumaric acid (1.1 equiv, 0.062 g) in methanol. Ifthe resulting solid contains impurities it may be recombined with themother liquor and purified on a UV Guided PrepHPLC (Flex) System andtreated with SC10-2 to give(2S)-2-[(S)-{[3-(3-chlorophenyl)pyridin-2-yl]thio}(phenyl)methyl]morpholineas a pale yellow oil (0.127 g, 65%). This oil is taken up in MeOH/DCM.To this is added a solution of fumaric acid (1.1 equiv, 0.0145 g) inmethanol, followed by Et₂O. The resulting crystals are collected byfiltration to give the fumarate salt of(2S)-2-[(S)-{[3-(3-chlorophenyl)pyridin-2-yl]thio}(phenyl)methyl]morpholine(1:1 fumarate salt) as a white solid (0.047 g). LCMS 12 min gradientmethod, Rt=5.7 min, (M+H⁺)=397

Example 4G(2S)-2-[{[3-(2-chlorophenyl)pyridin-2-yl]thio}(phenyl)methyl]morpholinefumarate

i) To palladium acetate (0.0025 g, 0.0011 mmole) in acetonitrile (3 ml),is added triphenylphosphine (0.0119 g, 0.045 mmole), under nitrogen, atroom temperature. The mixture is left to stir for 15 minutes. To thismixture is added water (distilled, 1 ml), 2-chlorophenylboronic acid(0.106 g, 0.68 mmole), 3-bromo-2-fluoropyridine (0.10 g, 0.57 mmole) andpotassium carbonate (0.470 g, 3.40 mmole). The reaction mixture isheated to 60° C. increasing to 75° C. over 5 hours then allowed to coolto room temperature. To the reaction mixture is added MeOH and this isloaded onto an SC10-2 column (10 g) preconditioned with MeOH. The columnis washed with MeOH and the resulting solution concentrated in vacuo togive an orange oil (0.196 g). The oil is purified by automated flashchromatography (ISCO System, a 10 g Redisep SiO₂ column, 0-30% ethylacetate in cyclohexane gradient elution over 40 minutes). This gave2-fluoro-3-(2-chlorophenyl)pyridine as a colourless oil (0.050 g, 42%).LCMS 6 min gradient method, Rt=3.3 min, (M+H⁺)=208

ii) To a solution of(S)-phenyl[(2S)-4-(phenylmethyl)morpholin-2-yl]methanethiol (6) (0.288g, 0.96 mmole) and 3-(2-chlorophenyl)-2-fluoropyridine (0.40 g, 1.93mmole) in dry, degassed DMF (2 ml) is added, under nitrogen, sodiumhydride (60% dispersion in oil, 0.0.046 g, 1.15 mmole). The mixture isleft to stir at room temperature over the weekend. The reaction mixtureis loaded directly onto an a 40 g Redisep SiO₂ column. Components areeluted using automated flash chromatography (ISCO System, 0-30% ethylacetate in cyclohexane gradient elution over 30 minutes at 40 ml/minuteflow rate) to give(2S)-2-[{[3-(2-chlorophenyl)pyridin-2-yl]thio}(phenyl)methyl]-4-(phenylmethyl)morpholineas a white solid (0.021 g, 5%). LCMS 6 min gradient method, Rt=4.3 min,(M+H⁺)=487.

iii) Deprotection of the morpholine nitrogen is carried out using themethod and work up as described in Example 1G, using polymer supporteddiisopropylamine (3.78 mmole/g, 0.057 g, 0.216 mmole),(2S)-2-[{[3-(2-chlorophenyl)pyridin-2-yl]thio}(phenyl)methyl]-4-(phenylmethyl)morpholine(0.021 g, 0.043 mmole), dry DCM (2 ml), 1-chloroethyl chloroformate(0.024 ml, 0.216 mmole) and methanol (2 ml). This gave a colourlessresidue (0.017 g, 100%). This residue is taken up in ethyl acetate. Tothis is added a solution of fumaric acid (1 equiv, 0.005 g) in methanol.This is reduced in volume and Et₂O added. The resulting solid iscollected by filtration to give the fumarate salt of(2S)-2-[{[3-(2-chlorophenyl)pyridin-2-yl]thio}(phenyl)methyl]morpholine(1:1 fumarate salt) as a pale green solid (0.012 g). LCMS 12 mingradient method, Rt=5.4 min, (M+H⁺)=397

Example 5G(2S)-2-((S)-phenyl{[3-(trifluoromethyl)pyridin-2-yl]thio}methyl)morpholine

i) Potassium fluoride (0.048 g, 0.84 mmole) and copper (I) iodide (0.159g, 0.84 mmole) are thoroughly mixed and dried under reduced pressurewith a hot air gun for 20 minutes. To the resulting yellow solid, atroom temperature is added(2S)-2-[(S)-[(3-iodopyridin-2-yl)thio](phenyl)methyl]-4-(phenylmethyl)morpholine(as prepared in Example 15) (0.190 g, 0.38 mmole) in anhydrous NMP (0.5ml) followed by anhydrous DMF (0.5 ml) then(trifluoromethyl)trimethylsilane (0.11 ml, 0.76 mmole). After 3 days atroom temperature, the temperature is increased to 50° C. The reactionmixture is heated at 50° C. overnight.

After cooling to room temperature, further(trifluoromethyl)trimethylsilane (0.11 ml, 0.76 mmole) is added to thereaction mixture and the mixture is left to stir overnight at roomtemperature. To the reaction mixture is added MeOH before loading ontoan SC10-2 column (10 g) preconditioned with MeOH. The column is washedwith MeOH. Basic material is eluted with 2 N NH₃/methanol. This isconcentrated in vacuo to give a pale yellow solid (0.199 g). This ispurified by automated flash chromatography (ISCO System, 3×4 g RedisepSiO₂ columns, in parallel, 0-20% ethyl acetate in cyclohexane gradientelution over 40 minutes) to give the(2S)-2-[(S)-[(3-iodopyridin-2-yl)thio](phenyl)methyl]-4-(phenylmethyl)morpholineas a white foam (0.108 g, 57% recovery of this starting material) and(2S)-2-((S)-phenyl{[3-(trifluoromethyl)pyridin-2-yl]thio}methyl)-4-(phenylmethyl)morpholineas a colourless oil (0.033 g, 20%). LCMS 6 min gradient method, Rt=4.2min, (M+H⁺)=445

ii) To a suspension of polymer supported diisopropylamine (3.72 mmol/g,0.097 g, 0.36 mmole) and(2S)-2-((S)-phenyl{[3-(trifluoromethyl)pyridin-2-yl]thio}methyl)-4-(phenylmethyl)morpholine(0.0.032 g, 0.07 mmole) in dry DCM (0.5 ml) is added 1-chloroethylchloroformate (0.039 ml, 0.36 mmole) at room temperature and undernitrogen. The mixture is heated at 40° C. for 2 hours. The reactionmixture is filtered and concentrated in vacuo then taken up in methanol(0.5 ml). The solution left to stir at room temperature overnight. Afterthis time, the reaction mixture is loaded directly onto an SC10-2column. The SC10-2 column is washed with methanol. The target compoundis eluted with 2 N NH₃/methanol. This is concentrated in vacuo to give apale yellow oil (0.024 g). The pale yellow oil is purified using anautomated PrepLCMS system, then liberated as the free base by treatmentwith SC10-2 and concentrated under vacuum to give(2S)-2-((S)-phenyl{[3-(trifluoromethyl)pyridin-2-yl]thio}methyl)morpholineas a white solid (0.005 g, 20%). LCMS 12 min gradient method, Rt=4.9min, (M+H⁺)=354

Example 6G(2S)-2-((S)-phenyl{[3-(phenylmethyl)pyridin-2-yl]thio}methyl)morpholinefumarate

i) To a 100 ml round-bottomed flask, under nitrogen, containing dry THF(25 ml) is added n-butyllithium (1.6 M solution in hexanes, 3.99 ml,6.39 mmole) at 0° C. followed by lithium diisopropylamide (2 M solutionin THF/n-heptane, 3.19 ml, 6.39 mmole). The reaction mixture is left tostir for 1 hour at 0° C. The mixture is cooled to −70° C. then2-fluoropyridine added. The solution is stirred at −70° C. for 4 hours.To the solution is added benzaldehyde (0.71 ml, 6.97 mmole). This isthen left to stir for 1 hour at −70° C., after which time water (100 ml)is added. On warming to room temperature the solution is extracted withchloroform (2×100 ml). The combined extracts are dried (Na₂SO₄) andconcentrated in vacuo to yield a yellow oil (1.58 g). Purification byautomated flash chromatography (ISCO System, Redisep 10 g SiO₂ column,0-30% ethyl acetate in cyclohexane gradient elution over 30 minutes at20 ml/min flow rate) gave 2-fluoro-3-(phenyl-1-hydroxymethyl)pyridine asa yellow oil (0.71 g, 59%). FIA (M+H⁺)=204

ii) To 5% Pd/C (0.07 g), under nitrogen, is added a solution of2-fluoro-3-(1-hydroxy-1-phenylmethyl)pyridine (0.71 g, 3.5 mmole) inethanol (50 ml). This is then put on a Parr Hydrogenator at 60 psi H₂and left over the weekend. The reaction mixture is filtered throughCelite®. Removal of solvent from the resulting solution gave a paleyellow oil. This is purified by automated flash chromatography (ISCOSystem, 10 g SiO₂ Redisep column, 0-30% ethyl acetate in cyclohexanegradient elution over 40 minutes at 20 ml/minute flow rate) to give2-fluoro-3-(phenylmethyl)pyridine as a colourless oil (0.18 g, 27%).

iii) To a solution of(S)-phenyl[(2S)-4-(phenylmethyl)morpholin-2-yl]methanethiol (6) (0.27 g,0.91 mmole) and 2-fluoro-3-(1-hydroxy-1-phenylmethyl)pyridine (0.17 g,0.91 mmole) in dry, degassed DMF (1.5 ml) is added, under nitrogen,sodium hydride (60% dispersion in oil, 0.07 g, 1.82 mmole). The mixtureis left to stir overnight at room temperature. A further portion ofsodium hydride (605 dispersion in oil, 0.07 g, 1.82 mmole) and DMF (1ml) is added. After 5 hours at room temperature, the reaction mixture istaken up in MeOH and loaded onto an SC10-2 column. The SC10-2 column iswashed with methanol. The(2S)-2-((S)-phenyl{[3-(phenylmethyl)pyridin-2-yl]thio}methyl)-4-(phenylmethyl)morpholineis eluted with 2 N NH₃/methanol. This is concentrated in vacuo to give ayellow residue (0.36 g). The residue is purified by automated flashchromatography (ISCO System, 35 g SiO₂ Redisep column, 0-30% ethylacetate in cyclohexane gradient elution over 40 minutes at 40 ml/minuteflow rate) which yields(2S)-2-((S)-phenyl{[3-(phenylmethyl)pyridin-2-yl]thio}methyl)-4-(phenylmethyl)morpholineas a pale yellow oil (0.10 g, 24%). LCMS 6 min gradient method, Rt=3.8min, (M+H⁺)=467

iv) Deprotection of the morpholine nitrogen is carried out using themethod and work up as described in Example 1G, using polymer supporteddiisopropylamine (3.78 mmole/g, 0.28 g, 1.07 mmole), of(2S)-2-((S)-phenyl{[3-(phenylmethyl)pyridin-2-yl]thio}methyl)-4-(phenylmethyl)morpholine(0.092 g, 0.20 mmole), dry DCM (5 ml), 1-chloroethyl chloroformate (0.12ml, 1.07 mmole) and methanol (5 ml). This gives (2S)-2-((S)-phenyl{[3-(phenylmethyl)pyridin-2-yl]thio}methyl)morpholine as a colourlessresidue (0.076 g, 94%). This oil is taken up in ethyl acetate. To thisis added a solution of fumaric acid (1.1 equiv, 0.026 g) in methanol.The resulting solution is concentrated in vacuo and the resulting oiltriturated with ethyl acetate. The solid is collected by filtration togive the fumarate salt of(2S)-2-((S)-phenyl{[3-(phenylmethyl)pyridin-2-yl]thio}methyl)morpholine(1:1 fumarate salt) as a white solid (0.070 g). LCMS 12 min gradientmethod, Rt=5.6 min, (M+H⁺)=377

Example 7G(2S)-2-((S)-phenyl{[3-(phenyloxy)pyridin-2-yl]thio}methyl)morpholinefumarate

i) To a 100 ml round bottomed flask is added 2-chloro-3-pyridinol (0.50g, 3.86 mmole), copper (II) acetate (0.70 g, 3.86 mmole), phenylboronicacid (0.94 g, 7.72 mmole) and powdered 4 Å molecular sieves. To themixture is added DCM (39 ml) followed by triethylamine (2.69 ml, 19.30mmole). This is stirred overnight, under nitrogen, at room temperature.The reaction mixture is poured into water (75 ml) and extracted withethyl acetate (3×75 ml). The combined extracts are concentrated in vacuoto give a brown oil (0.65 g). Purification by automated flashchromatography (ISCO System, Redisep 35 g SiO₂ column, 0-20% ethylacetate in cyclohexane gradient elution over 40 minutes) gives2-chloro-3-phenoxypyridine as a colourless oil (0.32 g, 41%). LCMS 6 mingradient method, Rt=3.6min, (M+H⁺)=206

ii) To a solution of(S)-phenyl[(2S)-4-(phenylmethyl)morpholin-2-yl]methanethiol (6) (0.352g, 1.18 mmole) and 2-chloro-3-phenoxypyridine (0.29 g, 1.41 mmole) indry, degassed DMF (3 ml) is added, under nitrogen, cesium fluoride(0.179 g, 1.18 mmole). The mixture is left to stir for two days at 55°C. A further portion of cesium fluoride (0.063 g, 0.41 mmole) is addedand the solution heated for 5 hours at 55° C. The reaction mixture isallowed to cool then loaded neat onto a 35 g SiO₂ Redisep column(preconditioned with cyclohexane). Automated flash chromatography (ISCOSystem, 0-40% ethyl acetate in cyclohexane gradient elution over 40minutes at 30 ml/minute flow rate) yields a yellow oil (2.26 g). This istaken up in MeOH and loaded onto an SC10-2 column. The SC10-2 column iswashed with methanol. The title compound is eluted with 2 NNH₃/methanol. This is concentrated in vacuo to give(2S)-2-{(S)-phenyl[(3-phenyloxypyridin-2-yl)thio]methyl}-4-(phenylmethyl)morpholineas a pale orange oil (0.092 g, 17%). LCMS 6 min gradient method, Rt=3.6min, (M+H⁺)=469

iii) Deprotection of the morpholine nitrogen is carried out using themethod and work up as described in Example 1G, using polymer supporteddiisopropylamine (3.78 mmole/g, 0.26 g, 0.98 mmole),(2S)-2-{(S)-phenyl[(3-phenyloxypyridin-2-yl)thio]methyl}-4-(phenylmethyl)morpholine(0.092 g, 0.20 mmole), dry DCM (5 ml), 1-chloroethyl chloroformate (0.11ml, 0.98 mmole) and methanol (5 ml). This gave(2S)-2-((S)-phenyl{[3-(phenyloxy)pyridin-2-yl]thio)methyl)morpholine asa pale yellow oil (0.070 g, 95%). This oil is taken up in ethyl acetate.To this is added a solution of ftimaric acid (1.1 equiv, 0.024 g) inmethanol. The resulting solution is concentrated in vacuo and theresulting oil triturated with ethyl acetate. The solid is collected byfiltration to give the fumarate salt of(2S)-2-((S)-phenyl{[3-(phenyloxy)pyridin-2-yl]thio}methyl)morpholine(1:1 fumarate salt) as an off-white solid (0.094 g). LCMS 12 mingradient method, R_(t)=5.5 min, (M+H⁺)=379

Example 8G(2S)-2-[(S)-[(3-chloropyridin-2-yl)thio](phenyl)methyl]morpholinefumarate

i) To a solution of(S)-phenyl[(2S)-4-(phenylmethyl)morpholin-2-yl]methanethiol (6) (0.446g, 1.49 mmole) and 2,3-dichloropyridine (0.246 g, 1.67 mmole) in dry,degassed DMF (3 ml) is added, under nitrogen, sodium hydride (60%dispersion in oil, 0.061 g, 1.53 mmole). The mixture is left to stirovernight at room temperature. The reaction mixture is taken up in MeOHand loaded onto an SC10-2 column. The SC10-2 column is washed withmethanol. The(2S)-2-[(S)-[(3-chloropyridin-2-yl)thio](phenyl)methyl]-4-(phenylmethyl)morpholineis eluted with 2 N NH₃/methanol. This is concentrated in vacuo to give(2S)-2-[(S)-[(3-chloropyridin-2-yl)thio](phenyl)methyl]-4-(phenylmethyl)morpholineas a pale yellow oil (0.61 g). LCMS 6 min gradient method, Rt=3.5 min,(M+H⁺)=411

ii) Deprotection of the morpholine nitrogen is carried out using themethod and work up as described in Example 1G, using polymer supporteddiisopropylamine (3.78 mmole/g, 0.39 g, 1.46 mmole),(2S)-2-[(S)-[(3-chloropyridin-2-yl)thio](phenyl)methyl]-4-(phenylmethyl)morpholine(0.120 g, 0.292 mmole), dry DCM (15 ml), 1-chloroethyl chloroformate(0.16 ml, 1.46 mmole) and methanol (15 ml). This gives(2S)-2-[(S)-[(3-chloropyridin-2-yl)thio](phenyl)methyl]morpholine as apale yellow oil (0.092 g, 98%). This oil is taken up in ethyl acetate.To this is added a solution of fumaric acid (1 equiv, 0.033 g) inmethanol. The resulting solution is concentrated in vacuo to give an oilwhich is crystallised from IPA. The solid is collected by filtration togive the fumarate salt of(2S)-2-[(S)-[(3-chloropyridin-2-yl)thio](phenyl)methyl]morpholine (1:1fumarate salt) as a white solid (0.111 g). LCMS 12 min gradient method,Rt=4.8 min, (M+H⁺)=321

Example 9G(2S)-2-[(S)-[(3-methylpyridin-2-yl)thio](phenyl)methyl]morpholinefumarate

i) To a degassed solution ofS-{(S)-phenyl[(2S)-4-(phenylmethyl)morpholin-2-yl]methyl}ethanethioate(5) (0.100 g, 0.293 mmole) and 2-fluoro-3-methylpyridine (0.325 g, 2.93mmole) in DMF (1 ml) is added sodium methoxide (0.016 g, 0.293 mmole).The reaction mixture is left to stir at room temperature, undernitrogen, overnight. The reaction mixture is diluted with methanol andloaded onto an SC10-2 (5 g) column preconditioned with MeOH. The columnis washed with MeOH then basic material is eluted with 2 N NH₃/methanol.This ammonia solution is concentrated in vacuo to give an orange oil(0.067 g) which is purified by automated flash chromatography (ISCOSystem, Redisep SiO₂ column, 0-20% ethyl acetate in cyclohexane gradientelution over 40 minutes) to give(2S)-2-[(S)-[(3-methylpyridin-2-yl)thio](phenyl)methyl]-4-(phenylmethyl)morpholineas a colourless oil (0.055 g, 44%). LCMS 6 min gradient method, Rt=2.9min, (M+H⁺)=391

ii) To a suspension of polymer supported diisopropylamine (3.78 mmol/g,0.167 g, 0.64 mmole) and(2S)-2-[(S)-[(3-methylpyridin-2-yl)thio](phenyl)methyl]-4-(phenylmethyl)morpholine(0.050 g, 0.13 mmole) in dry DCM (5 ml) is added 1-chloroethylchloroformate (0.070 ml, 0.64 mmole) at room temperature and undernitrogen. The mixture is heated at 40° C. for 1.5 hours. The reactionmixture is filtered and concentrated in vacuo then taken up in methanol(5 ml). The solution is left to stir at room temperature for 2.5 hours.After this time, the reaction mixture is loaded directly onto an SC10-2column. The SC10-2 column is washed with methanol. The free base of thetitle compound is eluted with 2 N NH₃/methanol. This ammonia solution isconcentrated in vacuo to give(2S)-2-[(S)-[(3-methylpyridin-2-yl)thio](phenyl)methyl]morpholine as anorange oil (0.037. g, 97%). This oil is taken up in methanol. To this isadded a solution of fumaric acid (1 equiv, 0.014 g) in methanol. This isstirred for a couple of minutes, then EtOAc followed by isohexane added.The resulting precipitate is collected by filtration to yield a whitesolid (0.048 g). This is recrystallised from ethyl acetate and isohexaneto give the fumarate salt of(2S)-2-[(S)-[(3-methylpyridin-2-yl)thio](phenyl)methyl]morpholine (1:1fumarate salt) as a white solid (0.013 g) LCMS 12 min gradient method,Rt=4.5 min, (M+H⁺)=301

Example 10G(2S)-2-[(S)-{[3-(4-chlorophenyl)pyridin-2-yl]thio}(phenyl)methyl]morpholinefumarate

i) To bis(benzonitrile)palladium(II)dichloride (0.054 g, 0.14 mmole) and1,4-bis(diphenylphosphine)butane (0.091 g, 0.21 mmole) is added drytoluene (6 ml), under nitrogen, and the mixture stirred for half anhour. To this is added 3-bromo-2-fluoropyridine (0.50 g, 2.83 mmole) inethanol (1.4 ml) followed by a solution of 4-chlorophenylboronic acid(0.887 g, 5.67 mmole) in ethanol (2.4 ml). To this is added an aqueoussolution of sodium carbonate (1 M, 2.83 ml, 2.83 mmole). The mixture isheated at 60° C. for 24 hours, then at 75° C. for a further 16 hours.The organic layer is loaded directly onto a 40 g Redisep SiO₂ column andcomponents isolated by automated flash chromatography (ISCO System,0-30% ethyl acetate in cyclohexane gradient elution over 40 minutes).This gave 3-(4-chlorophenyl)-2-fluoropyridine as a white solid (0.323 g,55%). LCMS 6 min gradient method, Rt=4.0 min, (M+H⁺)=208

ii) To a solution of(S)-phenyl[(2S)-4-(phenylmethyl)morpholin-2-yl]methanethiol (6) (0.388g, 1.30 mmole) and 3-(4-chlorophenyl)-2-fluoropyridine (0.323 g, 1.56mmole) in dry, degassed DMF (3 ml) is added, under nitrogen, cesiumfluoride (0.295 g, 1.94 mmole). The mixture is heated at 65° C. over theweekend. After this time, the reaction mixture is allowed to cool. Theresulting solid is taken up in MeOH/DCM and loaded directly onto anSC10-2 column. The SC10-2 column is washed with methanol followed by 2 NNH₃/methanol. The ammonia solution is concentrated in vacuo to give(2S)-2-[(S)-{[3-(4-chlorophenyl)pyridin-2-yl]thio}(phenyl)methyl]-4-(phenylmethyl)morpholineas an orange foam (0.514 g). This is purified by automated flashchromatography (ISCO System, 0-30% ethyl acetate in cyclohexane gradientelution over 40 minutes at 40 ml/minute flow rate) to give(2S)-2-[(S)-{[3-(4-chlorophenyl)pyridin-2-yl]thio}(phenyl)methyl]-4-(phenylmethyl)morpholineas a white foam (0.178 g, 28%). LCMS 6 min gradient method, Rt=4.2 min,(M+H⁺)=487

iii) Deprotection of the morpholine nitrogen is carried out using themethod and work up as described in Example 1G, using polymer supporteddiisopropylamine (3.78 mole/g, 0.48 g, 1.80 mmole),(2S)-2-[(S)-{[3-(4-chlorophenyl)pyridin-2-yl]thio}(phenyl)methyl]-4-(phenylmethyl)morpholine(0.175 g, 0.36 mmole), dry DCM (10 ml), 1-chloroethyl chloroformate(0.20 ml, 1.80 mmole) and methanol (10 ml). This gave a colourlessresidue (0.129 g, 90%). This residue is taken up in ethyl acetate. Tothis is added a solution of fumaric acid (1.1 equiv, 0.035 g) inmethanol. The resulting solid is recombined with the mother liquor andpurified on a UV Guided PrepHPLC (Flex) System and treated with SC10-2to give a yellow solid. This is further purified by automated flashchromatography (ISCO System, Redisep 4 g SiO₂ column, 0-5% methanol indichloromethane gradient elution over 40 minutes, then 10 minutes at 5%Methanol in dichloromethane with 10 ml/min flow rate) to give(2S)-2-[(S)-{[3-(4-chlorophenyl)pyridin-2-yl]thio}(phenyl)methyl]morpholineas a pale yellow oil (0.049 g, 34%). This oil is taken up in ethylacetate. To this is added a solution of fumaric acid (1.1 equiv, 0.0145g) in methanol. The resulting solution is concentrated in vacuo andrecrystallised from MeOH and Et₂O. The solid is collected by filtrationto give the fumarate salt of(2S)-2-[(S)-{[3-(4-chlorophenyl)pyridin-2-yl]thio}(phenyl)methyl]morpholine(1:1 fumarate salt) as a white solid (0.047 g). LCMS 12 min gradientmethod, Rt=5.7 min, (M+H⁺)=397

Example 11G(2S)-2-[(S)-[(5-bromopyridin-2-yl)thio](phenyl)methyl]morpholinefumarate

i) To a solution ofS-{(S)-phenyl[(2S)-4-(phenylmethyl)morpholin-2-yl]methyl}ethanethioate(5) (0.25 g, 0.73 mmole) in dry methanol (2 ml) is added sodiummethoxide (0.040 g, 0.73 mmole) under nitrogen. This is left to stir atroom temperature for 1 hour. Methanol is removed in vacuo and replacedwith DMF (1 ml). To this is then added the 5-bromo-2-fluoropyridine(0.11 ml, 1.02 mmole). The reaction mixture is left to stir at roomtemperature, under nitrogen, overnight. The reaction mixture is dilutedwith DCM and loaded directly onto a 35 g Redisep column. Purification byautomated flash chromatography (ISCO System, Redisep 35 g SiO₂ column,0-20% ethyl acetate in cyclohexane gradient elution over 40 minutes)gave(2S)-2-[(S)-[(5-bromopyridin-2-yl)thio](phenyl)methyl]-4-(phenylmethyl)morpholineas a colourless oil (0.186 g, 56%). LCMS 6 min gradient method, Rt=3.6min, (M+H⁺)=455/457

ii) To a suspension of polymer supported diisopropylamine (3.78 mmol/g,0.108 g, 20.4 mmole) and(2S)-2-[(S)-[(5-bromopyridin-2-yl)thio)(phenyl)methyl]-4-(phenylmethyl)morpholine(0.186 g, 0.408 mmole) in dry DCM (10 ml) is added 1-chloroethylchloroformate (0.22 ml, 2.04 mmole) at room temperature and undernitrogen. The mixture is heated at 40° C. for 2.5 hours. The reactionmixture is then filtered and concentrated in vacuo then taken up inmethanol (10 ml). The solution is left to stir at room temperatureovernight. After this time, the reaction mixture is loaded directly ontoan SC10-2 column (5 g). The SC10-2 column is washed with methanol. Thetarget compound is eluted with 2 N NH₃/methanol. This is concentrated invacuo to give(2S)-2-[(S)-[(5-bromopyridin-2-yl)thio](phenyl)methyl]morpholine as acolourless oil (0.108. g, 72%). This oil is taken up in ethanol. To thisis added a solution of fumaric acid (1.2 equiv, 0.041 g) in ethanol.Solvent is removed in vacuo and the resulting residue triturated withEtOAc. This solid is collected by filtration to give the fumarate saltof (2S)-2-[(S)-[(5-bromopyridin-2-yl)thio](phenyl)methyl]morpholine (1:1fumarate salt) as a white solid (0.105 g). LCMS 12 min gradient method,Rt=5.0 min, (M+H⁺)=365/367

Example 12G2-{[(S)-(2S)-morpholin-2-yl(phenyl)methyl]thio}pyridine-3-carboxamidefumarate

i) To a degassed solution ofS-{(S)-phenyl[(2S)-4-(phenylmethyl)morpholin-2-yl]methyl}ethanethioate(5) (0.100 g, 0.293 mmole) and 2-chloronicotinamide (0.046 g, 0.293mmole) in ethanol (3 ml) is added a solution of sodium hydroxide inwater (2 M, 0.293 ml, 0.586 mmole). The resulting solution is stirred atroom temperature overnight. An additional portion of2-chloronicotinamide (0.046 g, 0.293 mmole) is added to the reactionmixture which is then heated at 40° C. overnight. The reaction mixtureis diluted with methanol and loaded onto an SC10-2 column preconditionedwith MeOH. The column is washed with MeOH then basic material is elutedwith 2 N NH₃/methanol. This ammonia solution is concentrated in vacuo togive2-({[(S)-phenyl[(2S)-4-(phenylmethyl)morpholin-2-yl)methyl)thio)pyridine-3-carboxamideas a pale orange residue (0.124 g, 100%). LCMS 6 min gradient method,Rt=2.1 min, (M+H⁺)=420

ii) To a suspension of polymer supported diisopropylamine (3.78 mmol/g,0.38 g, 1.47 mmole) and2-({[(S)-phenyl[(2S)-4-(phenylmethyl)morpholin-2-yl)methyl}thio)pyridine-3-carboxamide(0.123 g, 0.29 mmole) in dry DCM (10 ml) is added 1-chloroethylchloroformate (0.16 ml, 1.47 mmole) at room temperature and undernitrogen. The mixture is heated at 40° C. for 2 hours. The reactionmixture is then filtered and concentrated in vacuo to give a pale yellowresidue. This is taken up in methanol (10 ml) and the solution left tostir at room temperature for 3 hours. After this time, the reactionmixture is loaded directly onto an SC10-2 column. The SC10-2 column iswashed with methanol then more basic compounds are eluted with 2 NNH₃/methanol. The ammonia solution is concentrated in vacuo to give2-{[(S)-(2S)-morpholin-2-yl(phenyl)methyl]thio}pyridine-3-carboxamide asa pale yellow oil (0.097 g, 100%). The pale yellow oil is taken up inmethanol. To this is added a solution of fumaric acid (1 equiv, 0.0153g) in methanol. This is stirred for a couple of minutes, then EtOAcadded. The resulting precipitate is collected by filtration to give thefumarate salt of2-{[(S)-(2S)-morpholin-2-yl(phenyl)methyl]thio}pyridine-3-carboxamide(1:1 fumarate salt) as a white solid (0.095 g). LCMS 12 min gradientmethod, Rt=2.4 min, (M+H⁺)=330

Example 13G2-{[(S)-(2S)-morpholin-2-yl(phenyl)methyl]thio}pyridine-3-carbonitrilefumarate

i) To a degassed solution ofS-{(S)-phenyl[(2S)-4-(phenylmethyl)morpholin-2-yl]methyl}ethanethioate(5) (0.050 g, 0.147 mmole) and 2-chloro-3-cyanopyridine (0.020 g, 0.146mmol) in ethanol (1.5 ml) is added a solution of sodium hydroxide inwater (2 M, 0.146 ml, 0.293 mmole). The resulting solution is stirred atroom temperature for ˜17 hours. The reaction mixture is diluted withmethanol and loaded onto an SC10-2 column preconditioned with MeOH. Thecolumn is washed with MeOH then basic material is eluted with 2 NNH₃/methanol. This ammonia solution is concentrated in vacuo to give2-({[(S)-phenyl[(2S)-4-(phenylmethyl)morpholin-2-yl]methyl}thio)pyridine-3-carbonitrileas an off white solid (0.055 g, 93%). LCMS 6 min gradient method, Rt≈2.8min, (M+H⁺)=402

ii) To a suspension of polymer supported diisopropylamine (3.78 mmol/g,0.181 g, 0.685 mmole) and2-({[(S)-phenyl[(25)-4-(phenylmethyl)morpholin-2-yl]methyl}thio)pyridine-3-carbonitrile(0.055 g, 0.137 mmole) in dry DCM (5 ml) is added 1-chloroethylchloroformate (0.075 ml, 0.685 mmole) at room temperature and undernitrogen. The mixture is heated at 40° C. for 2 hours. The reactionmixture is then filtered and concentrated in vacuo to give a pale orangeliquid. This is taken up in methanol (5 ml) and the solution left tostir at room temperature overnight. After this time, the reactionmixture is loaded directly onto an SC10-2 column. The SC10-2 column iswashed with methanol then more basic material is eluted with 2 NNH₃/methanol. The ammonia solution is concentrated in vacuo to give2-{[(S)-(2S)-morpholin-2-yl(phenyl)methyl]thio}pyridine-3-carbonitrileas a pale yellow oil (0.041 g, 95%). The pale yellow oil is taken up inmethanol. To this is added a solution of fumaric acid (1 equiv, 0.0153g) in methanol. This is stirred for a couple of minutes, then EtOAcfollowed by cyclohexane added. The resulting precipitate is collected byfiltration to give the fumarate salt of2-{[(S)-(2S)-morpholin-2-yl(phenyl)methyl]thio}pyridine-3-carbonitrile(1:1 fumarate salt) as a white solid (0.042 g). LCMS 12 min gradientmethod, Rt=4.6 min, (M+H⁺)=312

Example 14G (2S)-2-[phenyl(pyridin-2-ylthio)methyl]morpholinehydrochloride

i) To a stirred solution of(R)-phenyl[(2S)-4-(phenylmethyl)morpholin-2-yl]methyl methanesulfonate(0.70 g, 1.94 mmole) and 2-mercaptopyridine (0.54 g, 4.84 mmole) inanhydrous DMF, at room temperature and under nitrogen, is addedpotassium carbonate (0.80 g, 5.81 mmole). The reaction is left to stirat room temperature for 6 days. The reaction mixture is diluted withmethanol and loaded onto an SC10-2 column preconditioned with MeOH. Thecolumn is washed with MeOH then basic material is eluted with 2 NNH₃/methanol. This ammonia solution is concentrated in vacuo to give anorange residue (0.881 g). Purification by automated flash chromatography(ISCO System, 0-30% ethyl acetate in isohexane gradient elution over 30minutes) gave(2S)-2-[phenyl(pyridin-2-ylthio)methyl]-4-(phenylmethyl)morpholine as acolourless oil (0.245 g, 34%). LCMS 6 min gradient method, Rt=2.7 min,(M+H⁺)=377.

ii) Deprotection of the morpholine nitrogen is carried out using themethod and work up as described in Example 1G, using polymer supporteddiisopropylamine (3.78 mmole/g, 0.43 g, 1.64 mmole),(2S)-2-[phenyl(pyridin-2-ylthio)methyl]-4-(phenylmethyl)morpholine (0.103g, 0.274 mmole), dry DCM (10 ml), 1-chloroethyl chloroformate (0.15ml, 1.37 mmole) and methanol (10 ml). This gave a pale yellow oil (0.058g, 74%).). Purification of this residue by automated flashchromatography (ISCO System, SiO₂ Redisep column, 10% MeOH in DCM) gavea colourless oil (0.044 g, 54%). This oil is taken up in ethyl acetate.To this is added a solution of hydrochloric acid in dioxane (4 M, 0.1ml). Concentration in vacuo gave the hydrochloride salt of(2S)-2-[phenyl(pyridin-2-ylthio)methyl] as a white solid (0.045 g). LCMS6 min gradient method, Rt=1.8 min, (M+H⁺)=287

Example 15G(2S)-2-[(S)-[(3-iodopyridin-2-yl)thio](phenyl)methyl]morpholine fumarate

i) To (S)-phenyl[(2S)-4-(phenylmethyl)morpholin-2-yl]methanethiol (6)(0.50 g, 1.67 mmole) and 2-chloro-3-iodopyridine (0.48 g, 2.00 mmole) indegassed DMF (3 ml) is added cesium fluoride (0.38 g, 2.50 mmole) atroom temperature and under nitrogen. The mixture is heated at between55-75° C. for 3 days. The organic layer is then loaded directly onto a35 g ISCO column (SiO₂) and columned using automated flashchromatography (0-30% EtOAc in cyclohexane over 30 minutes) to give apale yellow crystalline solid (0.55 g). The solid is taken up inDCM:MeOH (1:1) and loaded onto an SC10-2 column (10 g) preconditionedwith MeOH. The column is washed with MeOH to remove2-chloro-3-iodopyridine, then more basic material is eluted with 2 NNH₃/methanol. The ammonia solution is concentrated in vacuo to give(2S)-2-[(S)-[(3-iodopyridin-2-yl)thio](phenyl)methyl]-4-(phenylmethyl)morpholineas a pale yellow solid (0.19 g, 23%). LCMS 6 min gradient method, Rt=3.8min, (M+H⁺)=503

ii) To a suspension of polymer supported diisopropylamine (3.72 mmol/g,0.285 g, 1.06 mmole) and(2S)-2-[(S)-[(3-iodopyridin-2-yl)thiol(phenyl)methyl]-4-(phenylmethyl)morpholine(0.107 g, 0.21 mmole) in dry DCM (1.5 ml) is added 1-chloroethylchloroformate (0.116 ml, 1.06 mmole) at room temperature and undernitrogen. The mixture is heated at 40° C. for 2 hours. The reactionmixture is then filtered and concentrated in vacuo to give a pale orangeliquid. This is taken up in methanol (1.5 ml) and the solution left tostir at room temperature overnight. After stirring overnight at roomtemperature, the reaction mixture is loaded directly onto an SC10-2column. The SC10-2 column is washed with methanol, then more basicmaterial is eluted with 2 N NH₃/methanol. The ammonia solution isconcentrated in vacuo to give(2S)-2-[(S)-[(3-iodopyridin-2-yl)thio](phenyl)methyl]morpholine as apale yellow oil (0.047 g, 53%). This oil is taken up in methanol and tothis is added a solution of fumaric acid (1 equiv, 0.013 g) in methanol.This is stirred for a couple of minutes, then EtOAc followed by Et₂Oadded. The resulting precipitate is collected by filtration to give thefumarate salt of(2S)-2-[(S)-[(3-iodopyridin-2-yl)thio](phenyl)methyl]morpholine (1:1fumarate salt) as a white solid (0.036 g). LCMS 12 min gradient method,Rt=4.9 min, (M+H⁺)=413

The pharmacological profile of the compounds of Formulae (IA), (IB),(IC), (ID), (IE), (IF) and (IG) can be demonstrated as follows. Thepreferred exemplified compounds above exhibit a K_(i) value less than500 nM at the norepinephrine transporter as determined using thescintillation proximity assay described below. Furthermore, thepreferred exemplified compounds above selectively inhibit thenorepinephrine transporter relative to the serotonin and dopaminetransporters by a factor of at least five using the scintillationproximity assays as described below.

Generation of Stable Cell-Lines Expressing the Human Dopamine,Norepinephrine and Serotonin Transporters

Standard molecular cloning techniques are used to generate stablecell-lines expressing the human dopamine, norepinephrine, and serotonintransporters. The polymerase chain reaction (PCR) was used in order toisolate and amplify each of the three full-length cDNAs from anappropriate cDNA library. Primers for PCR were designed using thefollowing published sequence data:

Human dopamine transporter: GenBank M95 167. Reference: Vandenbergh D J,Persico A M and Uhl G R. A human dopamine transporter cDNA predictsreduced glycosylation, displays a novel repetitive element and providesracially-dimorphic TaqI RFLPs. Molecular Brain Research (1992) Volume15, pages 161-166.

Human norepinephrine transporter: GenBank M65105. Reference: PacholczykT, Blakely, R D and Amara S G. Expression cloning of a cocaine- andantidepressant-sensitive human noradrenaline transporter. Nature (1991)Volume 350, pages 350-354.

Human serotonin transporter: GenBank L05568. Reference: Ramamoorthy S,Bauman A L, Moore K R, Han H, Yang-Feng T, Chang A S, Ganapathy V andBlakely R D. Antidepressant- and cocaine-sensitivehuman serotonintransporter: Molecular cloning, expression, and chromosomallocalization. Proceedings of the National Academy of Sciences of the USA(1993) Volume 90, pages 2542-2546.

The PCR products are cloned into a mammalian expression vector (e.g.,pcDNA3.1 (Invitrogen)) using standard ligation techniques. Theconstructs are then used to stably transfect HEK293 cells using acommercially available lipofection reagent (Lipofectamine™—Invitrogen)following the manufacturer's protocol.

Scintillation Proximity Assays for Determining the Affinity of TestLipands at the Norepinephrine Transporter

The compounds of Formulae (II) and (III) of the present invention arenorepinephrine reuptake inhibitors, and possess excellent activity in,for example, a scintillation proximity assay (e.g., J. Gobel, D. L.Saussy and A. Goetz, J. Pharmacol. Toxicol. (1999) 42:237-244). Thus,³H-nisoxetine binding to norepinephrine re-uptake sites in a cell linetransfected with DNA encoding human norepinephrine transporter bindingprotein has been used to determine the affinity of ligands at thenorepinephrine transporter.

Membrane Preparation:

Cell pastes from large scale production of HEK-293 cells expressingcloned human norepinephrine transporters were homogenized in 4 volumes50 mM Tris-HCl containing 300 mM NaCl and 5 mM KCl, pH 7.4. Thehomogenate was centrifuged twice (40,000 g, 10 min, 4° C.) with pelletre-suspension in 4 volumes of Tris-HCl buffer containing the abovereagents after the first spin and 8 volumes after the second spin. Thesuspended homogenate was centrifuged (100 g, 10 min, 4° C.) and thesupernatant kept and re-centrifuged (40,000 g, 20 min, 4° C.). Thepellet was resuspended in Tris-HCl buffer containing the above reagentsalong with 10% w/v sucrose and 0.1 mM phenylmethylsulfonyl fluoride(PMSF). The membrane preparation was stored in aliquots (1 ml) at −80°C. until required. The protein concentration of the membrane preparationwas determined using a bicinchoninic acid (BCA) protein assay reagentkit (available from Pierce).

[³H]-Nisoxetine Binding Assay:

Each well of a 96 well microtitre plate was set up to contain thefollowing:

-   50 μl 2 nM [N-methyl-³H]-Nisoxetine hydrochloride (70-87 Ci/mmol,    from NEN Life Science Products)-   75 μl Assay buffer (50 mM Tris-HCl pH 7.4 containing 300 mM NaCl and    5 mM KCl)-   25 μl Test compound, assay buffer (total binding) or 10 μM    Desipramine HCl (non-specific binding)-   50 μl Wheatgerm agglutinin coated poly (vinyltoluene) (WGA PVT) SPA    Beads (Amersham Biosciences RPNQ0001) (10 mg/ml)-   50 μl Membrane (0.2 mg protein per ml)

The microtitre plates were incubated at room temperature for 10 hoursprior to reading in a Trilux scintillation counter. The results wereanalysed using an automatic spline fitting programme (Multicalc,Packard, Milton Keynes, UK) to provide Ki values for each of the testcompounds.

Serotonin Binding Assay

The ability of a test compound to compete with [³H]-citalopram for itsbinding sites on cloned human serotonin transporter containing membraneshas been used as a measure of test compound ability to block serotoninuptake via its specific transporter (Ramamoorthy, S., Giovanetti, E.,Qian, Y., Blakely, R., (1998) J. Biol. Chem. 273: 2458).

Membrane Preparation:

Membrane preparation is essentially similar to that for thenorepinephrine transporter containing membranes as described above. Themembrane preparation was stored in aliquots (1 ml) at −70° C. untilrequired. The protein concentration of the membrane preparation wasdetermined using a BCA protein assay reagent kit.

[³H]-Citalopram Binding Assay:

Each well of a 96 well microtitre plate was set up to contain thefollowing:

-   50 μl 2 nM [³H]-Citalopram (60-86 Ci/mmol, Amersham Biosciences)-   75 μl Assay buffer (50 mM Tris-HCl pH 7.4 containing 150 mM NaCl and    5 mM KCl)-   25 μl Diluted compound, assay buffer (total binding) or 100 μM    Fluoxetine (non-specific binding)-   50 μl WGA PVT SPA Beads (40 mg/ml)-   50 μl Membrane preparation (0.4 mg protein per ml)

The microtitre plates were incubated at room temperature for 10 hoursprior to reading in a Trilux scintillation counter. The results wereanalysed using an automatic spline fitting programme (Multicalc,Packard, Milton Keynes, UK) to provide Ki (nM) values for each of thetest compounds.

Dopamine Binding Assay

The ability of a test compound to compete with [³ H]-WIN35,428 for itsbinding sites on human cell membranes containing cloned human dopaminetransporter has been used as a measure of the ability of such testcompounds to block dopamine uptake via its specific transporter(Ramamoorthy et al 1998 supra).

Membrane Preparation:

Is essentially the same as for membranes containing cloned humanserotonin transporter as described above.

[³H]-WIN35,428 Binding Assay:

Each well of a 96 well microtitre plate was set up to contain thefollowing:

-   50 μl 4 nM [³H]-WIN35,428 (84-87 Cl/mmol, from NEN Life Science    Products)-   75 μl Assay buffer (50 mM Tris-HCl pH 7.4 containing 150 mM NaCl and    5 mM KCl)-   25 μl Diluted compound, assay buffer (total binding) or 100 μM    Nomifensine (non-specific binding)-   50 μl WGA PVT SPA Beads (10 mg/ml)-   50 μl Membrane preparation (0.2 mg protein per ml.)

The microtitre plates were incubated at room temperature for 120 minutesprior to reading in a Trilux scintillation counter. The results wereanalysed using an automatic spline fitting programme (Multicalc,Packard, Milton Keynes, UK) to provide Ki values for each of the testcompounds.

Acid Stability

The acid stability of a compound according to the present invention wasdetermined as a solution in buffer at 6 different pH values (HCl 0.1 N,pH 2, pH 4, pH 6, pH 7, and pH 8) at 40° C. over a time course of 72hours. Samples were taken at the beginning of the study and after 3, 6and 24 hours and analysed by capillary electrophoresis. The originalsample used in this study contained 0.8% of the undesired epimer asinternal standard. The samples taken at the different time points duringthe study did not show any significant change in the percentage of theundesired epimer. This assay confirms that compounds of the presentinvention are chemically and configurationally stable under acidicconditions.

In Vitro Determination of the Interaction of Compounds with CYP2D6 inHuman Hepatic Microsomes

Cytochrome P450 2D6 (CYP2D6) is a mammalian enzyme which is commonlyassociated with the metabolism of around 30% of pharmaceuticalcompounds. Moreover, this enzyme exhibits genetic polymorphism,resulting in the presence of both normal and poor metabolizers in thepopulation. A low involvement of CYP2D6 in the metabolism of compounds(i.e. the compound being a poor substrate of CYP2D6) is desirable inorder to reduce any variability from subject to subject in thepharmacokinetics of the compound. Also, compounds with a low inhihibitorpotential for CYP2D6 are desirable in order to avoid drug-druginteractions with co-administered drugs that are substrates of CYP2D6.Compounds can be tested both as substrates and as inhibitors of thisenzyme by means of the following assays.

CYP2D6 Substrate Assay

Principle:

This assay determines the extent of the CYP2D6 enzyme involvement in thetotal oxidative metabolism of a compound in microsomes. Preferredcompounds of the present invention exhibit less than 75% totalmetabolism via the CYP2D6 pathway.

For this in vitro assay, the extent of oxidative metabolism in humanliver microsomes (HLM) is determined after a 30 minute incubation in theabsence and presence of Quinidine, a specific chemical inhibitor ofCYP2D6. The difference in the extent of metabolism in absence andpresence of the inhibitor indicates the involvement of CYP2D6 in themetabolism of the compound.

Materials and Methods:

Human liver microsomes (mixture of 20 different donors, mixed gender)were acquired from Human Biologics (Scottsdale, Ariz., USA). Quinidineand β-NADPH (β-Nicotinamide Adenine Dinucleotide Phosphate, reducedform, tetrasodium salt) were purchased from Sigma (St Louis, Mo., USA).All the other reagents and solvents were of analytical grade. A stocksolution of the new chemical entity (NCE) was prepared in a mixture ofAcetonitrile/Water to reach a final concentration of acetonitrile in theincubation below 0.5%.

The microsomal incubation mixture (total volume 0.1 mL) contained theNCE (4 μM), μ-NADPH (1 mM), microsomal proteins (0.5 mg/mL), andQuinidine (0 or 2 μM) in 100 mM sodium phosphate buffer pH 7.4. Themixture was incubated for 30 minutes at 37° C. in a shaking waterbath.The reaction was terminated by the addition of acetonitrile (75 μL). Thesamples were vortexed and the denaturated proteins were removed bycentrifugation. The amount of NCE in the supernatant was analyzed byliquid chromatography /mass spectrometry (LC/MS) after addition of aninternal standard. A sample was also taken at the start of theincubation (t=0), and analysed similarly.

Analysis of the NCE was performed by liquid chromatography/massspectrometry. Ten μL of diluted samples (20 fold dilution in the mobilephase) were injected onto a Spherisorb CN Column, 5 μM and 2.1 mm×100 mm(Waters corp. Milford, Mass., USA). The mobile phase consisting of amixture of Solvent A/Solvent B, 30/70 (v/v) was pumped (Alliance 2795,Waters corp. Milford, Mass., USA) through the column at a flow rate of0.2 ml/minute. Solvent A and Solvent B were a mixture of ammoniumformate 5.10⁻³ M pH 4.5/methanol in the proportions 95/5 (v/v) and 10/90(v/v), for solvent A and solvent B, respectively. The NCE and theinternal standard were quantified by monitoring their molecular ionusing a mass spectrometer ZMD or ZQ (Waters-Micromass corp, Machester,UK) operated in a positive electrospray ionisation.

The extent of CYP2D6 involvement (% of CYP2D6 involvement) wascalculated comparing the extent of metabolism in absence and in presenceof quinidine in the incubation.The  extent  of  metabolism  without    inhibitor  (%)  was  calculated  as  follows:$\frac{\begin{matrix}{{\left( {{NCE}\quad{response}\quad{in}\quad{samples}\quad{without}\quad{inhibitor}} \right)\quad{time}\quad 0} -} \\{\left( {{NCE}\quad{response}\quad{in}\quad{samples}\quad{without}\quad{inhibitor}} \right)\quad{time}\quad 30}\end{matrix}}{\left( {{NCE}\quad{response}\quad{in}\quad{samples}\quad{without}\quad{inihbitor}} \right)\quad{time}\quad 0} \times 100$The  extent  of  metabolism  with  inhibitor  (%)  was  calculated  as  follows:$\frac{\begin{matrix}{{\left( {{NCE}\quad{response}\quad{in}\quad{samples}\quad{without}\quad{inhibitor}} \right)\quad{time}\quad 0} -} \\{\left( {{NCE}\quad{response}\quad{in}\quad{samples}\quad{with}\quad{inihbitor}} \right)\quad{time}\quad 30}\end{matrix}}{\left( {{NCE}\quad{response}\quad{in}\quad{samples}\quad{without}\quad{inhibitor}} \right)\quad{time}\quad 0} \times 100$where the NCE response is the area of the NCE divided by the area of theinternal standard in the LC/MS analysis chromatogram, time0 and time30correspond to the 0 and 30 minutes incubation time.

The % of CYP2D6 involvement was calculated as follows:$\frac{\begin{matrix}{\left( {\%\quad{extent}\quad{of}\quad{metabolism}\quad{without}\quad{inhibitor}} \right) -} \\\left( {\%\quad{extent}\quad{of}\quad{metabolism}\quad{with}\quad{inhibitor}} \right)\end{matrix}}{\%\quad{extent}\quad{of}\quad{metabolism}\quad{without}\quad{inhibitor}} \times 100$CYP2D6 Inhibitor Assay

Principle:

The CYP2D6 inhibitor assay evaluates the potential for a compound toinhibit CYP2D6. This is performed by the measurement of the inhibitionof the bufuralol 1′-hydroxylase hydroxylase activity by the compoundcompared to a control. The 1′-hydroxylation of bufuralol is a metabolicreaction specific to CYP2D6. Preferred compounds of the presentinvention exhibit an IC₅₀ higher than 6 μM for CYP2D6 activity, the IC₅₀being the concentration of the compound that gives 50% of inhibition ofthe CYP2D6 activity.

Materials and Methods:

Human liver microsomes (mixture of 20 different donors, mixed gender)were acquired from Human Biologics (Scottsdale, Ariz.). β-NADPH waspurchased from Sigma (St Louis, Mo.). Bufuralol was purchased fromUltrafine (Manchester, UK). All the other reagents and solvents were ofanalytical grade.

Microsomal incubation mixture (total volume 0.1 mL) contained bufuralol10 μM, β-NADPH (2 mM), microsomal proteins (0.5 mg/mL), and the newchemical entity (NCE) (0, 5, and 25 μM) in 100 mM sodium phosphatebuffer pH 7.4. The mixture was incubated in a shaking waterbath at 37°C. for 5 minutes. The reaction was terminated by the addition ofmethanol (75 μL). The samples were vortexed and the denaturated proteinswere removed by centrifugation. The supernatant was analyzed by liquidchromatography connected to a fluorescence detector. The formation ofthe 1′-hydroxybufuralol was monitored in control samples (0 μM NCE) andin the samples incubated in presence of the NCE. The stock solution ofNCE was prepared in a mixture of Acetonitrile/Water to reach a finalconcentration of acetonitrile in the incubation below 1.0%.

The determination of 1′hydroxybufuralol in the samples was performed byliquid chromatograhy with fluorimetric detection as described below.Twenty five μL samples were injected onto a Chromolith PerformanceRP-18e column (100 mm×4.6 mm) (Merck KGAa, Darmstadt, Germany). Themobile phase, consisting of a mixture of solvent A and solvent B whosethe proportions changed according the following linear gradient, waspumped through the column at a flow rate of 1 ml/min: Time (minutes)Solvent A (%) Solvent B (%) 0 65 35 2.0 65 35 2.5 0 100 5.5 0 100 6.0 6535

Solvent A and Solvent B consisted of a mixture of 0.02 M potassiumdihydrogenophosphate buffer pH3/methanol in the proportion 90/10 (v/v)for solvent A and 10/90 (v/v) for solvent B. The run time was 7.5minutes. Formation of 1′-hydroxybufuralol was monitored by fluorimetricdetection with extinction at λ 252 nm and emission at λ 302 nm.

The IC₅₀ of the NCE for CYP2D6 was calculated by the measurement of thepercent of inhibition of the formation of the 1′-hydroxybufuralol inpresence of the NCE compared to control samples (no NCE) at a knownconcentration of the NCE.

-   -   The percent of inhibition of the formation of the        1′-hydroxybufuralol is calculated as follows:        $\frac{\begin{matrix}        {\left( {1^{\prime}\text{-}{hydroxybufuralol}\quad{formed}\quad{without}\quad{inhibitor}} \right) -} \\        \left( {1^{\prime}\text{-}{hyfroxybufuralol}\quad{formed}\quad{with}\quad{inhibitor}} \right)        \end{matrix}}{\left( {1^{\prime}\text{-}{hydroxybufuralol}\quad{area}\quad{formed}\quad{without}\quad{inhibitor}} \right)} \times 100$

The IC₅₀ is calculated from the percent inhibition of the formation ofthe 1′-hydroxybufuralol as follows (assuming competitive inhibition):$\frac{{NCE}\quad{Concentration} \times \left( {100 - {{Percent}\quad{of}\quad{inhibition}}} \right)}{{Percent}\quad{of}\quad{inhibition}}$

The IC₅₀ estimation is assumed valid if inhibition is between 20% and80% (Moody G C, Griffin S J, Mather A N, McGinnity D F, Riley R J.(1999) Fully automated analysis of activities catalyzed by the majorhuman liver cytochrome P450 (CYP) enzymes: assessment of human CYPinhibition potential. Xenobiotica 29(1): 53-75).

The invention being thus described, it is obvious that the same can bevaried in many ways. Such variations are not to be regarded as adeparture from the spirit and scope of the present invention, and allsuch modifications as would be obvious to one skilled in the art areintended to be included within the scope of the following claims.

1. A method of treating stuttering or another communication disorder,comprising administering to a patient in need of such treatment aneffective amount of a norepinephrine reuptake inhibitor selected fromthe group consisting of atomoxetine or a pharmaceutically acceptablesalt thereof and a compound of formula (I):

wherein X is C₁-C₄ alkylthio, and Y is C₁-C₂ alkyl, or apharmaceutically acceptable salt thereof.

is a group of formula (a) or (b)


2. (canceled)
 3. The method of claim 1, wherein said norepinephrinereuptake inhibitor is atomoxetine hydrochloride.